BACKGROUND: Atherosclerosis is the principle cause of cardiovascular disease. Due to their spontaneous development of atherosclerosis, apolipoprotein E knockout mice (ApoEKO) are one of the best studied animal models of atherosclerosis. Although previous reports have evaluated the effects of omega-3 fatty acids in the prevention of cardiovascular disease, little is known on their effects in the setting of ApoE deficiency. OBJECTIVE: To assess the cardiovascular effects of omega-3 fatty acid supplementation (fish oil, flaxseed oil, and designer oil) in ApoEKO mice maintained on a high fat diet. METHODOLOGY: A total of 40 six-week old ApoEKO mice were randomized into 4 treatment groups. All animals were fed a Western-type diet reconstituted with either safflower oil (control), fish oil, flaxseed oil or designer oil. In vivo cardiac function was assessed weekly using echocardiography. Blood pressure and plasma lipid levels were serially measured. Cardiac remodeling was examined using histological analysis and biochemical assessment of a cardiac biomarker: brain natriuretic peptide (BNP). RESULTS: Echocardiography demonstrated increased ventricular wall thickness in the fish oil treated mice, as compared to the control group (p<0.05). Blood pressure increased over time in the fish oil treated mice (p<0.05). Relative to control, the fish oil group also showed increased plasma triglycerides (p<0.01), and decreased plasma total cholesterol (p<0.05). Furthermore, ventricular BNP expression was elevated in the fish oil treated mice (p<0.05). Flaxseed oil and designer oil produced similar cardiovascular effects as the control diet. CONCLUSION: A high fat diet supplemented with fish oil leads to adverse cardiovascular effects in ApoE deficient mice.