Background: We sought to determine patient factors associated with adherence and response to a manualized supportive psychotherapy designed for pregnant and postpartum women with major depressive disorder (MDD). Methods: Supportive psychotherapy was provided to all participants in parallel to a placebo-controlled trial of omega-3 fatty acids. The supportive psychotherapy was a six-session, manualized intervention. Clinicians recorded participation and adherence. Symptom rating scales were completed at baseline and every 2 weeks and included the Hamilton Depression Rating Scale (HAM-D) as the primary outcome. N=59 participants were enrolled. Subjects were referred by obstetrical and pediatric health-care providers. Descriptive statistics and general linear models were used to assess the study outcomes. Results: The mean number of completed sessions was 4.4 out of a full course of 6. There were no significant differences found between omega-3 fatty acid and placebo groups in the parallel assessments. We found significantly lower adherence to the psychotherapy sessions for women who were not married, were unemployed, and those with higher scores on the HAM-D at baseline. Completion of a greater number of psychotherapy sessions, lower baseline depression scores, and postpartum status (compared with pregnant status) were associated with lower final HAM-D scores. Overall, the response rate was 52.9% (≥50% decrease on HAM-D scores), and the remission rate (final score<8) was 31.4%. Conclusions: Study limitations included small sample size, and possible nonspecific and placebo effects. Adherence appears important in response to supportive psychotherapy in women with perinatal MDD, and future efforts to improve adherence in perinatal women with MDD are warranted. Depression and Anxiety, 2010. © 2009 Wiley-Liss, Inc.