CONTEXT: Studies of depressed psychiatric patients have shown that antidepressant efficacy can be increased by augmentation with omega-3 fatty acids. OBJECTIVE: To determine whether omega-3 improves the response to sertraline in patients with major depression and coronary heart disease (CHD). DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial. Between May 2005 and December 2008, 122 patients in St Louis, Missouri, with major depression and CHD were randomized. INTERVENTIONS: After a 2-week run-in period, all patients were given 50 mg/d of sertraline and randomized in double-blind fashion to receive 2 g/d of omega-3 acid ethyl esters (930 mg of eicosapentaenoic acid [EPA] and 750 mg of docosahexaenoic acid [DHA]) (n=62) or to corn oil placebo capsules (n=60) for 10 weeks. MAIN OUTCOME MEASURES: Scores on the Beck Depression Inventory (BDI-II) and the Hamilton Rating Scale for Depression (HAM-D). RESULTS: Adherence to the medication regimen was 97% or more in both groups for both medications. There were no differences in weekly BDI-II scores (treatment x time interaction = 0.02; 95% confidence interval [CI], -0.33 to 0.36; t(112) = 0.11; P = .91), pre-post BDI-II scores (placebo, 14.8 vs omega-3, 16.1; 95% difference-in-means CI, -4.5 to 2.0; t(116) = -0.77; P = .44), or HAM-D scores (placebo, 9.4 vs omega-3, 9.3; 95% difference-in-means CI, -2.2 to 2.4; t(115) = 0.12; P = .90). The groups did not differ on predefined indicators of depression remission (BDI-II < or = 8: placebo, 27.4% vs omega-3, 28.3%; odds ratio [OR], 0.96; 95% CI, 0.43-2.15; t(113) = -0.11; P = .91) or response (> 50% reduction in BDI-II from baseline: placebo, 49.0% vs omega-3, 47.7%; OR, 1.06; 95% CI, 0.51-2.19; t(112) = 0.15; P = .88). CONCLUSIONS: Treatment of patients with CHD and major depression with sertraline and omega-3 fatty acids did not result in superior depression outcomes at 10 weeks, compared with sertraline and placebo. Whether higher doses of omega-3 or sertraline, a different ratio of EPA to DHA, longer treatment, or omega-3 monotherapy can improve depression in patients with CHD remains to be determined. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00116857.