Background: Epidemiological and clinical studies suggest that increased intake of eicosapentaenoic acid (EPA) alleviates unipolar depression. Aims: To examine the efficacy of EPA in treating depression in bipolar disorder. Method: In a 12-week, double-blind study individuals with bipolar depression were randomly assigned to adjunctive treatment with placebo (n=26) or with 1 g/day (n=24) or 2 g/day (n=25) of ethyl-EPA. Primary efficacy was assessed by the Hamilton Rating Scale for Depression (HRSD), with changes in the Young Mania Rating Scale and Clinical Global Impression Scale (CGI) as secondary outcome measures. Results: There was no apparent benefit of 2 g over 1 g ethyl-EPA daily. Significant improvement was noted with ethyl-EPA treatment compared with placebo in the HRSD (P=0.04) and the CGI (P=0.004) scores. Both doses were well tolerated. Conclusions: Adjunctive ethyl-EPA is an effective and well-tolerated intervention in bipolar depression.