BACKGROUND: It is suggested that a low intake of fish and/or n-3 PUFA is associated with depressed mood. However, results from epidemiologic studies are mixed, and randomized trials have mainly been performed in depressed patients, yielding conflicting results. OBJECTIVE: We investigated the effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on mental well-being in a double-blind, placebo-controlled trial. DESIGN: Independently living individuals (n = 302) aged >=65 y were randomly assigned to consume 1800 mg/d EPA+DHA, 400 mg/d EPA+DHA, or placebo capsules for 26 wk. Changes in mental well-being were assessed as the primary outcome with the Center for Epidemiologic Studies Depression Scale (CES-D), Montgomery-Åsberg Rating Scale (MADRS), Geriatric Depression Scale (GDS-15), and Hospital Anxiety and Depression Scale (HADS-A). RESULTS: Plasma concentrations of EPA+DHA increased by 238% in the high-dose and 51% in the low-dose fish-oil group compared with the placebo group, reflecting excellent compliance. Baseline CES-D scores ranged from 5.9 to 6.8 in the 3 groups and were not significantly different between groups. Mean changes in CES-D scores after 26 wk were -0.2, 0.2, and -0.4 (P = 0.87) in the high-dose fish oil, low-dose fish oil, and placebo groups, respectively. Treatment with neither 1800 mg nor 400 mg EPA+DHA differentially affected any of the measures of mental well-being after 13 or 26 wk of intervention compared with placebo. CONCLUSIONS: In this randomized, double-blind, placebo-controlled trial we observed no effect of EPA+DHA supplementation for 26 wk on mental well-being in the general older population studied. This trial was registered at clinicaltrials.gov as NCT00124852.