The prevention of major depression is an important research goal which deserves increased attention. Depressive symptoms and disorders are particularly common in primary care patients and have a negative impact on functioning and well-being comparable with other major chronic medical conditions. The San Francisco Depression Prevention Research project conducted a randomized, controlled, prevention trial to demonstrate the feasibility of implementing such research in a public sector setting serving low-income, predominantly minority individuals: 150 primary care patients free from depression or other major mental disorders were randomized to an experimental cognitive-behavioral intervention or to a control condition. The experimental intervention group reported a significantly greater reduction in depressive levels. Decline in depressive levels was significantly mediated by decline in the frequency of negative conditions. Group differences in the number of new episodes (incidence) of major depression did not reach significance during the 1-year trial. We conclude that depression prevention trials in public sector primary care settings are feasible, and that depressive symptoms can be reduced even in low-income, minority populations. To conduct randomized prevention trials that can test effects on incidence with sufficient statistical power, subgroups at greater imminent risk have to be identified.