There are few data evaluating plasma and/or peripheral blood monocyte cytokine concentrations/production or attempts to manipulate proinflammatory cytokines in nonalcoholic steatohepatitis (NASH). A pilot project in a general clinical research center evaluated the effects of a step 1 American Heart Association diet plus aerobic exercise with or without 800 IU of vitamin E daily on cytokine profiles and liver enzyme levels in 16 patients with biopsy-proven NASH. Biochemical assessment of liver function, lipid profiles, and body mass index significantly improved during the first 6 weeks of therapy and remained stable during the following 6 weeks. Plasma hyaluronic acid (HA) concentrations decreased in parallel with weight loss. Plasma tumor necrosis factor (TNF) concentrations were significantly elevated in patients with NASH and similar to patients with stable alcoholic cirrhosis but not as elevated as in patients with acute alcoholic steatohepatitis (AH). Although plasma TNF, interleukin 8 (IL-8), and IL-6 concentrations were all significantly elevated compared with control values, only plasma IL-6 levels significantly decreased with therapy. Peripheral blood monocyte TNF, IL-8, and IL-6 production was significantly elevated in patients with NASH but did not significantly decrease. Independent effects of vitamin E were not observed in this small sample. In conclusion, patients with NASH have dysregulated cytokine metabolism similar to, but less pronounced than abnormalities documented in AH. Cytokine values generally did not decrease significantly with weight loss with or without vitamin E over the duration of the study. Lifestyle modifications (low-fat diet and exercise) were associated with improvement in liver enzymes, cholesterol, and plasma HA levels in patients with NASH, whereas the level of vitamin E supplementation used in this short-term pilot study provided no apparent added benefit.