OBJECTIVE A randomized controlled trial was conducted to evaluate the efficacy of a cognitive-behavioral (CBT) intervention to prevent perinatal depression in high-risk Latinas. METHOD A sample of 217 participants, predominantly low-income Central American immigrants who met demographic and depression risk criteria, were randomized into usual care (UC; n = 105) or an 8-week CBT group intervention during pregnancy and 3 individual booster sessions during postpartum (n = 112). Participants completed measures assessing depressive symptoms (Center for Epidemiological Studies Depression Scale at baseline; Beck Depression Inventory, Second Edition [BDI-II]) and major depressive episodes (Mood Screener) at 5 time points throughout the perinatal period. RESULTS Intent-to-treat analyses indicated that intervention participants had significantly lower depressive symptoms and fewer cases of moderate depression (BDI-II ≥ 20) at Time 2 than UC participants. These effects were stronger for women who fully participated in the intervention (≥ 4 classes). The cumulative incidence of major depressive episodes was not significantly different between the intervention (7.8%) and UC (9.6%) groups. CONCLUSIONS A CBT intervention for low-income, high-risk Latinas reduced depressive symptoms during pregnancy but not during the postpartum period. Low levels of depressive symptoms and lower than expected rates of clinical depression in both groups may partially be due to methodological issues. As perinatal depression is a significant public health problem, more work is needed to prevent perinatal depression in low-income, ethnically diverse women.