Impoverished minority women experience a higher burden from depression than do white women because they are less likely to receive appropriate care. Little is known about the effectiveness of guideline-based care for depression with impoverished minority women, most of whom do not seek care. To determine the impact of an intervention to deliver guideline-based care for depression compared with referral to community care with low-income and minority women. A randomized controlled trial conducted in the Washington, DC, suburban area from March 1997 through May 2002 of 267 women with current major depression, who attended county-run Women, Infants, and Children food subsidy programs and Title X family planning clinics. Outcomes Hamilton Depression Rating Scale measured monthly from baseline through 6 months; instrumental role functioning (Social Adjustment Scale) and social functioning (Short Form 36-Item Health Survey) measured at baseline and 3 and 6 months. Participants were randomly assigned to an antidepressant medication intervention (trial of paroxetine switched to buproprion, if lack of response) (n = 88), a psychotherapy intervention (8 weeks of manual-guided cognitive behavior therapy) (n = 90), or referral to community mental health services (n = 89). Both the medication intervention (P<.001) and the psychotherapy intervention (P =.006) reduced depressive symptoms more than the community referral did. The medication intervention also resulted in improved instrumental role (P =.006) and social (P =.001) functioning. The psychotherapy intervention resulted in improved social functioning (P =.02). Women randomly assigned to receive medications were twice as likely (odds ratio, 2.04; 95% confidence interval, 0.98-4.27; P =.057) to achieve a Hamilton Depression Rating Scale score of 7 or less by month 6 as were those referred to community care. Guideline-concordant care for major depression is effective for these ethnically diverse and impoverished patients. More women engaged in a sufficient duration of treatment with medications compared with psychotherapy, and outcome gains were more extensive and robust for medications.