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Future Private Practice series regulars Amy Brenneman, Paul Adelstein, Tim Daly, Taye Diggs, Chris Lowell starred in the twenty-second and twenty-third episodes of the season, portraying Violet Turner, Cooper Freedman, Peter Wilder, Sam Bennett and William "Dell" Parker, respectively, in order to make the transition to the proposed spin-off.The interns of Seattle Grace Hospital help Izzie cope with the loss of her fiancé, Denny Duquette as well as her decision to quit the internship program.Ellen Pompeo portrayed Meredith Grey, both the protagonist and the narrator of the series, whose main goal is achieving a balance between the difficulties of the internship, and the complicated relationships in her private life.Katherine Heigl portrayed intern Isobel "Izzie" Stevens, mourning the death of her fiancé as she unexpectedly decides to quit her job; she concludes that she is too personally involved with her patients. Knight played the role of intern George O'Malley, who gradually becomes more self-confident after his feelings for Meredith diminish.Whereas the first season mainly focused on the impact the surgical field has on the main characters, and the second one provided a detailed perspective on the physicians' private lives, the third season deals with the tough challenges brought by the last phase of the surgeons' internship, combining the professional motif emphasized in the first season, with the complex personal background used in the second.Through the season, several new storylines are introduced, including the arrival of Dane's character, Dr.Actors Ellen Pompeo, Sandra Oh, Katherine Heigl, Justin Chambers, and T. Knight reprised their roles as surgical interns Meredith Grey, Cristina Yang, Izzie Stevens, Alex Karev, and George O'Malley, respectively, continuing their expansive storylines as focal points throughout the season.
(Jeffrey Dean Morgan) appeared in two episodes of the season, during Meredith's limbo sequence.
Elizabeth Reaser portrayed Rebecca "Ava" Pope, recurring character and love interest for Alex Karev.