The effect of feeding fish oil (Menhaden) on the progression of rhesus monkey atherosclerosis was determined by feeding diets containing 2% cholesterol and either 25% coconut oil (Group I), 25% fish oil/coconut oil (1:1) (Group II), or 25% fish oil/coconut oil (3:1) (Group III) for 12 months (n = 8/group). The average serum cholesterol levels were 875 mg/dl for Group I, 463 mg/dl for Group II, and 405 mg/dl for Group III. HDL cholesterol levels were 49 mg/dl for Group I, 29 mg/dl for Group II, and 20 mg/dl for Group III. An average of 79% of the aortic intima was involved with atherosclerosis in Group I, 48% in Group II, and 36% in Group III. The aortas of both fish-oil groups (II or III) contained significantly less cholesterol (total, free, and esterified), as well as less acid lipase, cholesteryl esterase, and ACAT activities when compared to the coconut-oil group (I) (p less than 0.05). Microscopically, the aortic and carotid artery lesions were smaller in cross-sectional area and in thickness, and contained less macrophages in the fish-oil groups (II and III) when compared to the coconut-oil group (I) (p less than 0.05). This protective effect was not consistently enhanced by increasing the proportion of fish oil to 3:1 (Group III) over 1:1 (Group II). The results indicate that fish oil-containing diets reduce serum cholesterol levels and inhibit atherosclerosis even in the face of lowered HDL cholesterol levels when compared to a pure coconut oil/cholesterol diet in rhesus monkeys. Therefore, fish-oil diets exert effective protective control of progression of atherosclerosis during severe atherogenic stimuli.