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Alex Karev secured a position in the surgical residency program at Seattle Grace after graduating from University of Iowa medical school. A mixer was held for the new interns, and it was at this mixer that he met and presumably hit it off with nurse Olivia Harper, as he is shown leaving the event with an arm around her.

On his first day, he managed to rub everyone the wrong way, insulting his fellow interns and treating the nurses badly. He branded George O'Malley, 'license to kill' when he froze up during his first surgery, and called Meredith Grey a nurse. Only wanting to work on interesting surgical cases, Alex was flippant towards the other patients that he deemed uninteresting. Because of this, he wrongly diagnosed a patient with pulmonary embolus as having pneumonia. He was promptly pulled off the case by Chief of Surgery, Dr. Richard Webber. Alex was subsequently reassigned to a new resident Dr. Miranda Bailey, to the disdain of the other interns under her. His frequent sexist remarks and overt come-ons made him even more disliked by the interns, who proceeded to dub him evil spawn. He became even more hated when he hijacked an open-heart surgery that rightfully belonged to the other interns. After which, he proceeded to taunt a furious Meredith who attacked him in retaliation, calling him a frat boy bitch.

Alex often caused a great deal of hurt and pain through his actions, intentionally or otherwise. When Alex found out that Izzie Stevens was an ex-lingerie model, he obtained a copy of her advertisement and proceeded to paste copies all over Seattle Grace. Although he succeeded in humiliating her, she turned things on him by stripping to her underwear in front of him and several other interns, reminding him that her modeling is the reason why she is debt-free while he is sitting on two hundred grand of student loan. Despite the callous image he projects, Alex is particularly affected when he treats addicts and abused children because of his childhood background. He initially refused to install a central line for a Demerol addict because he did not want to feed his habit. Alex then revealed to Izzie that his father was a musician addicted to heroin. He was also able to connect with a teenage boy, whose abusive father hit his mother in Enough is Enough. In Izzie's presence, he related to the boy how he became a wrestler so that he could beat up his father when he attacked his mother, and that he always regretted that decision. Izzie realized that Alex was not as insensitive and cruel as he portrayed himself to be. She began a tentative friendship with him, to the shock of Meredith, Cristina and George. Later, Meredith's opinion of Alex changed for the better when he offered to listen to her problems with her mother, Ellis.

In Whos Zoomin Who, George contracted syphilis from Alex through Olivia. It was revealed that Olivia was already dating Alex when George asked her out. Olivia subsequently broke up with Alex after realizing how much she liked George. Furious at the revelation that Alex was the cause of his syphilis, George punched Alex in the face. That night, Joe, the owner of Emerald City Bar was admitted to Seattle Grace Hospital, and in discussions with Joe it was revealed that Alex was a regular at Joe's bar every night and that he and Joe had become close friends. When George finds a way to pay for Joe's hospital bills, the animosity between George and Alex is dissolved after Alex gives George a hug.

Alex eventually asked Izzie out on a date in Deny, Deny, Deny. However on that very day, he found out from the Chief that he failed his medical board exams. This caused him to suffer from a crisis of confidence, leading him to treat her shabbily during their date. His confidence took another blow when he froze up during a makeshift emergency surgery in an elevator during a power outage, and George had to operate on the patient himself. Izzie, still furious from the horrendous date, refused to speak to him. Afterwards in Joe's bar, he went up to her and kissed her passionately, rekindling their budding relationship. However, their sex life hit a bump when Alex had difficulties performing. Meanwhile, his confidence in his medical skills further deteriorated after he accidentally administered a wrong dosage saline solution, paralyzing the patient. In a moment of vulnerability, he slept with Olivia and was caught in the act by Izzie, effectively ending their relationship. Alex confided in Meredith about his failed medical boards and she decided to help him study, roping in Cristina and George to help as well. Izzie subsequently found out about it and blew up at her friends for helping Alex. She eventually forgave him, but ruled out getting back together with him. Alex passed his re-test and became a full-fledged doctor. In Its the End of the World, the dire situation of a bomb scare caused Izzie to realize that she should act on her feelings. She accosted Alex and the two proceeded to have sex in a linen closet. They continued to sleep together several times over the course of the day.

In What Have I Done to Deserve This, Izzie's patient Denny Duquette was re-admitted after he suffered a heartfailure. Alex was jealous of Izzies concern for Denny, and tried to get Denny to back off by telling him that he was with Izzie and there is a good chance that he would die from his failing heart anyway. She confronted him, and he told her that she cannot get involved with her patients. However, Izzie realized that she didn't have to settle for Alex. Offended when Alex referred to the still-living Denny as a "corpse", she dumped him saying, "Just so were clear, were over. On your very best day, that 'corpse' is twice the man you will ever be. You're not good enough for me, Alex. You're not good enough for anyone."

Alex's streak of brutal honesty caused Addison to be on the receiving end of legal action, when he persuaded a patients husband to sue the hospital for Addisons mistake in Blues for Sister Someone. Furious, she informs a stunned Alex that he would be placed permanently under her service. Despite his lack of interest in obstetrics and gynecology, he has exhibited some flair for it as he managed to deliver a premature baby by himself.

When Denny died from a stroke, Alex picked up a devastated Izzie and told her that the dead man was no longer Denny, the man she once loved. In Staring at the Sun, Alex realized that his feelings for Izzie had not diminished since she dumped him, and impulsively kissed her in the stairwell. Izzie had yet to get over Denny and told him she cannot commit in a relationship with him just yet, and he understood. However in "Scars and Souvenirs", Alex claimed his lack of interest in Izzie and has appeared to have gotten over her.

When acclaimed plastic surgeon Dr. Mark Sloan (McSteamy) took up a position at Seattle Grace, Alex leapt at the chance to pursue his interest in plastics. He wanted Addison to release him from her service, and she did, but not before telling him that he would miss her. It becomes clear that Mark is a poor teacher, only delegating menial tasks to Alex. Alex gradually developed distaste for plastics after serving as Marks intern, and found himself drawn back to Addisons surgeries. Meanwhile, Addison discovered Alexs better side and found herself attracted to him. To some degree, Alex was also attracted to Addison as they subsequently shared frequent meaningful looks. This culminated in an actual kiss in Joes bar. However, he later told her that he only wants to work with her professionally, and is not interested in pursuing a romantic relationship with her.

During a ferry accident, Alex found a severely injured pregnant woman crushed under a pylon. He rescued her from the debris, and encouraged her to stay alive. The pregnant Jane Doe subsequently became hysterical after realizing she could not remember anything, and turned to Alex for support, thinking that he was her husband. Alex showed much concern for her and constantly checked on her progress, bonding with her in the process. He also helped her pick out a new face for reconstruction, as well as a new name "Ava". As Alex spent more time with Ava, he became increasingly attached to her, spending most of his time checking on her progress and doing research. This led Addison to accuse him of being too emotionally involved with a patient, but he countered saying that he was just being prepared. In the heat of the argument, Addison kissed him and pushed him into an on-call room, where the two had sex. However, Alex rebuffed Addison's subsequent advances, after learning she wanted a committed man to have kids with, something which he was not ready for.

Alex and Ava grew closer, as he helped her through the many surgeries she had to undergo, including the delivery of her daughter. Ava subsequently makes a reference about her baby inheriting her father's nose, causing a suspicious Alex to confront her about amnesia. She admitted to regaining her lost memories and revealed that she was stuck in a bad marriage and had decided to leave her husband. Appalled at her willingness to leave all her friends and family for a new life, Alex forced her to tell him her real identity. Although she initially refused, she later told him her real name - Rebecca Pope.

Not long after, Rebecca's husband came to Seattle Grace looking for her. Rebecca was due for discharge, but begged Alex to give her a reason from him to stay. Feeling that he was not good enough for her, Alex told Rebecca to return to her husband's side. He then headed to Cristina's wedding where he hit on Addison. Addison told him that he did not want her because he wanted Rebecca, and urged him to find her. However, he returned to the hospital, only to find Rebecca's room empty.