Background: The optimum way to improve the recognition and treatment of postnatal depression in developing countries is uncertain. We compared the effectiveness of a multicomponent intervention with usual care to treat postnatal depression in low-income mothers in primary-care clinics in Santiago, Chile. Methods: 230 mothers with major depression attending postnatal clinics were randomly allocated to either a multicomponent intervention (n=114) or usual care (n=116). The multicomponent intervention involved a psychoeducational group, treatment adherence support, and pharmacotherapy if needed. Usual care included all services normally available in the clinics, including antidepressant drugs, brief psychotherapeutic interventions, medical consultations, or external referral for specialty treatment. The primary outcome measure was the Edinburgh postnatal depression scale (EPDS) score at 3 and 6 months after randomisation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00518830. Findings: 208 (90%) of women randomly assigned to treatment groups completed assessments. The crude mean EPDS score was lower for the multicomponent intervention group than for the usual care group at 3 months (8·5 [95% CI 7·2-9·7] vs 12·8 [11·3-14·1]). Although these differences between groups decreased by 6 months, EPDS score remained better in multicomponent intervention group than in usual care group (10·9 [9·6-12·2] vs 12·5 [11·1-13·8]). The adjusted difference in mean EPDS between the two groups at 3 months was -4·5 (95% CI -6·3 to -2·7; p<0·0001). The decrease in the number of women taking antidepressants after 3 months was greater in the intervention group than in the usual care group (multicomponent intervention from 60/101 [59%; 95% CI 49-69%] to 38/106 [36%; 27-46%]; usual care from 18/108 [17%; 10-25%] to 11/102 [11%; 6-19%]). Interpretation: Our findings suggest that low-income mothers with depression and who have newly born children could be effectively helped, even in low-income settings, through multicomponent interventions. Further refinements to this intervention are needed to ensure treatment compliance after the acute phase.