To examine the interaction between dietary fat and vitamin E at the level of the rat immune system, a 2 x 3 factorial study was designed. Weanling female Sprague Dawley rats were fed for 8-9 wk diets that contained either corn oil (CO diet) or fish oil (FO diet) and one of three levels (30, 300, 900 mg/kg) of all-rac-alpha-tocopheryl acetate. At the lowest level of dietary vitamin E, alpha-tocopherol content of splenocytes from FO-fed rats was approximately 40% lower (P < 0.05) than in those from CO-fed rats. Supplementation with all-rac-alpha-tocopheryl acetate elevated alpha-tocopherol in splenocytes from FO-fed rats but not in those from CO-fed rats, and reduced the relative proportion of arachidonic acid and eicosapentaenoic acid in the serum of CO-fed and FO-fed rats, respectively. Prostaglandin E production by isolated immune cells was not affected by all-rac-alpha-tocopheryl acetate supplementation. However, feeding the FO diet consistently reduced prostaglandin E synthesis by 70-80% as compared with the CO diet. Antibody production against sheep RBC was highest in rats fed the FO diet supplemented with 900 mg all-rac-alpha-tocopheryl acetate/kg of diet. However, antibody response was not directly correlated to diet-induced changes in immune cell prostaglandin E production or alpha-tocopherol content. Our data suggest that there are significant interactions between vitamin E and (n-3) fatty acids that affect the immune system and that further research in this area is warranted. J. Nutr. 122: 1009-1018, 1992.