Based on the putative relationship between depleted omega-3 fatty acids and postpartum depression, we initiated an open-label pilot study of omega-3 fatty acid supplementation with the aim of preventing postpartum depression. Euthymic pregnant females with a past history of depression in the postpartum period were started on 2960 mg of fish oil (1.4:1 eicosapentaenoic acid:docosahexaenoic acid) per day between the 34th to 36th week of pregnancy and assessed through 12 weeks postpartum. Four of seven participants had a depressive episode during the study period. No participants withdrew from the study due to adverse events. This preliminary, small, open-label pilot study failed to show promising results for the use of omega-3 fatty acid monotherapy beginning at 34 to 36 weeks gestation for the prevention of postpartum depression in patients with a prior postpartum depression history. Controlled studies are lacking.