Cytokines may be involved in weight loss and disturbances of metabolism associated with human immunodeficiency virus (HIV) infection. Dietary n-3 fatty acids reduce the production of interleukin-1 (IL-1) and tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMC) in normal humans and prevent IL-1 and TNF anorexia in animals. Accordingly, we studied the nutritional and metabolic effects of a 10-week trial of dietary fish oil (MaxEPA 18 g/day) in men with weight loss due to acquired immune deficiency syndrome (AIDS). Twenty men were enrolled, and 16 completed the 10-week supplementation period. Prior weight loss was 13.7 +/- 1.8 kg(17.4 +/- 1.6% body weight, means +/- SE). Food intake, body composition, blood chemistries, serum cytokine concentrations, in vitro production of IL-1 and TNF by PBMC, and clinical course were followed. A subset of subjects (n=12) underwent stable isotope infusions to measure de novo hepatic lipogenesis (DNL), an in vivo metabolic index that is influenced by cytokine presence and has previously been found to be elevated in AIDS. An unsupplemented group of men with AIDS wasting (10.4 +/- 2.4 kg weight loss, 13.1 +/- 2.2% body weight) was monitored for 10 weeks as controls. Baseline food intake (2,395 +/- 177 kcal/day and 95.1 +/- 7.2 g protein/day), body weight, percent fat, and fat-free mass were unchanged over the 10-week supplementation period. Serum triglycerides were reduced in hypertriglyceridemic subjects, confirming compliance with fish oil supplementation and suggesting that their hypertriglyceridemia was at least in part due to overproduction. Serum TNF and IL-1 were undetectable before or after fish oil supplementation. Serum interferon alpha (IFN) was measurable but did not change. In vitro production of IL-1 and TNF by PBMC was markedly reduced both at baseline and after fish oil supplementation in this population, even in the presence of new AIDS complications, compared with normal controls. The metabolic measurement DNL fell and weight was gained (2.1 +/- 1.3 kg) in subjects who did not develop new AIDS-related complications, but further increases in DNL and further weight loss were observed in subjects who developed a new AIDS complication (p<0.05 for interaction between new complication and change in DNL). No changes in body weight, food intake, serum triglycerides, serum cytokines, or DNL were observed in the unsupplemented group. We conclude that fish oil is a weak anticytokine agent that is unable to overcome the metabolic and nutritional consequences of acute AIDS-related complications but may exert a clinical anticytokine effect in stable AIDS patients. Cytokine production by PBMC is not a useful or reliable marker of in vivo cytokine activity in AIDS patients with weight loss. In contrast, an integrative functional index that is sensitive to cytokine presence in tissues (hepatic DNL) correlated with clinical response. These findings are relevant to the design of future studies of more potent anticytokine agents, such as thalidomide.