Controversy exists as to whether eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) or both are responsible for the efficacy of n-3 polyunsaturated fatty acids in depression. We conducted a single-center, randomized, double-blind, placebo-controlled, multi-arm, parallel-group trial, comparing the efficacy of EPA versus DHA as adjuvants to maintenance medication treatments for mild-to-moderate depression. Eighty-one mild-to-moderately depressed outpatients were randomly assigned to receive either 1 g/d of EPA or DHA or placebo (coconut oil) for 12 weeks. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS) final score in the modified intention-to-treat population, which comprised of all randomized patients with at least 1 post-randomization observation (n=62; 61.3% female; mean age 35.1 +/- 1.2 years). Allocated treatments were well tolerated. Although there was no significant difference between groups at baseline, patients in the EPA group showed a significantly lower mean HDRS score at study endpoint compared with those in the DHA (p= 50% decrease from the baseline HDRS score) was only observed in 6 patients receiving EPA, while no one in any of DHA or placebo groups responded to treatment. Overall, these data suggest greater efficacy of EPA compared to DHA or placebo as an adjunctive treatment in mild-to-moderate depression. However, further, randomized controlled trials are needed to support these findings. (C) 2012 Elsevier B.V. and ECNP. All rights reserved.