Immunosuppression observed in chronic alcohol users is caused by multiple factors including the amount of alcohol consumed and alcohol-induced nutritional deficiencies. Investigators of the immunotoxic effects of ethanol (ETOH) frequently concentrate on the effects of ETOH and neglect nutrition as a confounding variable. This study investigated the immunotoxic effects of ETOH under variable dietary nutritional conditions. Mice were fed diets containing various levels of nutrients and ethanol for 7 weeks. Spleen cell number, and interleukin-2 and tumor necrosis factor (TNF) secretion were independent of the diet consumed, but were affected by consumption of ETOH. Body and spleen weights, and interferon-gamma secretion were modulated by ETOH as well as by diet. The results indicate that the nutritional composition of the diet consumed during concurrent administration of ETOH modulates the immunotoxic effects of chronic ETOH ingestion. We conclude that the levels of various nutrients in animal diets have to be planned and controlled carefully in order to identify directly the immunotoxic effects of ETOH.