Genetic moderation of interpersonal psychotherapy (IPT) efficacy for economically disadvantaged women with major depressive disorder was examined. Specifically, we investigated whether genotypic variation in corticotropin releasing hormone receptor 1 (CRHR1) and the linked polymorphic region of the serotonin transporter gene (5-HTTLPR) moderated effects of IPT on depressive symptoms over time. We also tested genotype moderation of IPT mechanisms on social adjustment and perceived stress. Non-treatment-seeking urban women at or below the poverty level with infants were recruited from the community (N = 126; M age = 25.33 years, SD = 4.99; 54.0% African American, 22.2% Caucasian, and 23.8% Hispanic/biracial) and randomized to individual IPT or Enhanced Community Standard groups. The results revealed that changes in depressive symptoms over time depended on both intervention group and genotypes (5-HTTLPR and CRHR1). Moreover, multiple-group path analysis indicated that IPT improved depressive symptoms, increased social adjustment, and decreased perceived stress at posttreatment among women with the 0 copies of the CRHR1 TAT haplotype only. Finally, improved social adjustment at postintervention significantly mediated the effect of IPT on reduced depressive symptoms at 8 months postintervention for women with 0 copies of the TAT haplotype only. Post hoc analyses of 5-HTTLPR were indicative of differential susceptibility, albeit among African American women only.