We investigated the effects of omega-3 fatty acids administration on endothelium-dependent vasodilation in patients > or =65 years old who received treatment for chronic heart failure (CHF). Twenty patients (mean age 73 years; 15 men) with grade II and III CHF who were on maximal medical management were recruited. Patients were randomized in a double-blind, crossover fashion to 6 weeks of omega-3 fatty acid (1.8 g ecosapentaenoic acid and 1.2 g docosahexaenoic acid) or olive oil. Forearm blood flow (FBF) responses to incremental doses of intra-arterial sodium nitroprusside, acetycholine (ACH), angiotensin-II, and N(g)-nitro-L-arginine methyl ester were assessed by venous occlusion strain gauge plethysmography. The endothelium-dependent increase in FBF was greater in response in ACH infusion after omega-3 fatty acid administration (7.9, 95% confidence interval [CI] 4.81 to 11.08 to 11.3, 95% CI 7.31 to 15.23 arbitrary units (p <0.05) compared with baseline (7.95, 95% CI 4.8 to 11.08 arbitrary units) and olive oil administration (7.27, 95% CI 4.66 to 9.88 arbitrary units) (p = NS for both). Neither omega-3 fatty acid nor olive oil altered endothelium-independent vasodilation in response to infusion of sodium nitroprusside, nor did they influence vasoconstrictor responses to angiotensin-II or N(g)-nitro-L-arginine methyl ester. Dietary omega-3 fatty acid supplementation was accompanied by an increase in FBF response to ACH, which represents enhanced endothelium-dependent vasodilation in CHF. Further studies are warranted to assess the mechanism responsible for the beneficial actions of omega-3 fatty acids in CHF.