Objective: Promising results were obtained in an earlier pilot study of a preventive intervention based on the principles of interpersonal psychotherapy to reduce the risk of postpartum major depressive disorder. In this study, the authors examined whether the intervention would reduce the risk of postpartum major depressive disorder in a larger sample of pregnant women. Method: Ninety-nine pregnant women on public assistance who were assessed to be at risk for postpartum depression were randomly assigned to receive standard antenatal care plus the intervention or standard antenatal care only. Diagnostic interviews were administered 3 months after delivery to assess for major depressive disorder. Results: Within 3 months after delivery, eight (20%) of the women in the standard antenatal care condition had developed postpartum major depressive disorder, compared with two (4%) in the intervention condition. Conclusions: This study provides further evidence for the efficacy of a brief intervention to reduce the occurrence of major depressive disorder among financially disadvantaged women during a postpartum period of 3 months.