Fish oils, high in omega-3 fatty acids, affect lipid and carbohydrate metabolism partly through their effects on the levels of hormones involved in their metabolism. Recently, a role for opiates in glucose homeostasis and lipid metabolism has been reported. It is possible that some of the effects offish oils on carbohydrate and lipid metabolism may be, in part, mediated through changes in opiates. We therefore studied the effects offish oil and fish oil plus vitamin E, a potent antioxidant, on plasma opiates and adrenocorticotrophic hormone (ACTH) in normal subjects. Forty healthy men consumed diets providing 40% of energy from fat and a minimum of 25 mg vitamin E for 28 weeks. During the first 10 weeks, diets were supplemented with placebo, 15 g mixed fat~day. During the second 10 weeks, placebo was replaced by 15 g/day offish oil concentrate. During the last 8 weeks, 200 U/day of vitamin E was added to fish oil. Plasma opioid peptides were measured by radioimmunoassay after eluting from C~8 Sep-Pak cartridges. Fish oil feeding significantly decreased plasma ~-endorphin compared with placebo, but had no significant effects on plasma ACTH, met-, and leu-enkephalins. Fish oil plus vitamin E appeared to further decrease ~-endorphin and significantly increased both enkephalins. Thus, it is possible that in addition to hormonal changes, alterations in opiate tone may also partly explain the effect offish oil and vitamin E on plasma glucose, triglyceride, and other metabolic and physiologic processes.