Objectives Depression during pregnancy is one of the strongest predictors of postpartum depression, which, in turn, has deleterious, lasting effects on infant and child well-being and on the mother’s and father’s mental health. The primary question guiding this randomized controlled trial was, Does culturally relevant, enhanced brief interpersonal psychotherapy (IPT-B) confer greater advantages to low-income, pregnant women than those that accrue from enhanced usual care in treating depression in this population? Enhanced IPT-B is a multicomponent model of care designed to treat antenatal depression and consists of an engagement session, followed by eight acute IPT-B sessions before the birth and maintenance IPT up to six months postpartum. IPT-B was specifically enhanced to make it culturally relevant to socioeconomically disadvantaged women. Methods Fifty-three non–treatment-seeking, pregnant African-American and white patients receiving prenatal services in a large, urban obstetrics and gynecology clinic and meeting criteria for depression on the Edinburgh Postnatal Depression Scale (score >12 on a scale of 0 to 30) were randomly assigned to receive either enhanced IPT-B (N=25) or enhanced usual care (N=28), both of which were delivered in the clinic. Participants were assessed before and after treatment on depression diagnoses, depressive symptoms, and social functioning. Results Intent-to-treat analyses showed that participants in enhanced IPT-B, compared with those in enhanced usual care, displayed significant reductions in depression diagnoses and depressive symptoms before childbirth (three months postbaseline) and at six months postpartum and showed significant improvements in social functioning at six months postpartum. Conclusions Findings suggest that enhanced IPT-B ameliorates depression during pregnancy and prevents depressive relapse and improves social functioning up to six months postpartum.