BACKGROUND: Clinicians and researchers have questioned whether participants in randomized control trials (RCTs) are representative of patients in the broader clinical population. METHOD: We compared the demographic, clinical, and personality characteristics of patients (N=256) with major depressive disorder (MDD) receiving antidepressant medication or interpersonal therapy as part of an RCT investigation (n=105) versus in a clinic (n=151). The RCT and clinic protocols were identical with the exception of recruitment procedures (advertisement versus physician referral) and assignment to treatment (randomized versus nonrandomized). RESULTS: No significant differences emerged between the RCT participants and clinic patients for sex, age, marital status, and education. Overall, clinic patients were no more severely depressed compared to RCT participants; there was, however, a significant interaction effect. Response rates were significantly higher for RCT participants versus clinic patients. Those participating in the RCT scored significantly higher on a personality scale assessing preference for novel experiences compared to those in the clinic. CONCLUSIONS: Differences in clinical and personality variables between those receiving treatment for MDD as part of an RCT versus in a clinic exist; however, the clinical significance of these differences remains in question, as these variables were unrelated to treatment outcome.