Background: Low brain-derived neurotrophic factor (BDNF) levels are observed in both depressed and diabetes patients. Animal research has shown that omega-3 polyunsaturated fatty acids increase BDNF levels. In this exploratory randomized double-blind placebo-controlled study in diabetes patients with major depression, we tested whether (a) omega- 3 ethyl-eicosapentaenoic acid (E-EPA) leads to increased serum BDNF levels and (b) whether changes in BDNF levels are associated with corresponding changes in depression. Methods: Patients received 1 g/day E-EPA (n = 13) or placebo (n = 12) for 12 weeks, in addition to ongoing antidepressant therapy. At baseline and 12-week follow-up, we determined serum BDNF levels and depression severity, using the Montgomery-sberg Depression Rating Scale. Results: We found no effect of E-EPA on BDNF levels (t = -0.144, p = 0.887), and changes in BDNF levels and depression severity were not significantly associated (Spearman's ρ = -0.115, p = 0.593). Conclusion: Our study does not provide evidence that supplementation with E-EPA improves BDNF levels in depressed diabetes patients already using antidepressants. Copyright © 2011 S. Karger AG, Basel.