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Objective: Phase III clinical trials for depression enroll participants with major depressive disorder according to stringent inclusion and exclusion criteria. These patients may not be representative of typical depressed patients seeking treatment. This analysis used data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project—which used broad inclusion and minimal exclusion criteria—to evaluate whether phase III clinical trials recruit representative depressed outpatients. Method: Of 2,855 participants, 22.2% met typical entry criteria for phase III clinical trials (efficacy sample) and 77.8% did not (nonefficacy sample). These groups were compared regarding baseline sociodemographic and clinical features and the characteristics and outcomes of acute-phase treatment. Results: The efficacy sample had a shorter average duration of illness and lower rates of family history of substance abuse, prior suicide attempts, and anxious and atypical symptom features. Despite similar medication dosing and time at exit dose, the efficacy participants tolerated citalopram better. They also had higher rates of response (51.6% versus 39.1%) and remission (34.4% versus 24.7%). These differences persisted even after adjustments for baseline differences. Conclusions: Phase III trials do not recruit representative treatment-seeking depressed patients. Broader phase III inclusion criteria would increase the generalizability of results to practice, potentially reducing placebo response and remission rates (reducing the risk of failed trials) but at the risk of some increase in adverse events.