To determine whether the cytokine tumor necrosis factor/cachectin might be a mediator of hepatotoxicity seen after exposure to polyhalogenated aromatic hydrocarbons, rats treated with a single dose of 3,3′,4,4′-tetrabromobiphenyl (150 μmol/kg intraperitoneally) or corn oil vehicle were studied. The 3,3′,4,4′-tetrabromobiphenyl caused the expected anorexia, alterations in organ weights and changes in cytochromes P-450 over 21 days. Although tumor necrosis factor could not be detected in the serum of rats at any time after 3,3′,4,4′-tetrabromobiphenyl treatment alone (from 90 min to 21 days), 3,3′,4,4′-tetrabromobiphenyl treatment significantly increased peak serum tumor necrosis factor concentrations after intravenous bacterial endotoxin (lipopolysaccharide, 1 mg/kg). This effect was seen with lipopolysaccharide given 24 hr, 48 hr, and 20 days after 3,3′,4,4′-tetrabromobiphenyl treatment and increases in peak serum tumor necrosis factor levels ranged from threefold to eightfold over controls in various experiments with no significant differences between the three time points. However, a synergistic increase in hepatic damage (assessed by serum enzymes and liver histological findings 24 hr after lipopolysaccharide injection) was seen in rats given lipopolysaccharide 24 hr and 48 hr after 3,3′,4,4′-tetrabromobiphenyl administration, with 75% and 25% lethality, respectively. There was no lethality with lipopolysaccharide given 20 days after 3,3′,4,4′-tetrabromobiphenyl administration or with simultaneous administration. A lower dose of lipopolysaccharide (0.1 mg/kg) given 24 hr after 3,3′,4,4′-tetrabromobiphenyl also enhanced hepatotoxicity and serum tumor necrosis factor but without lethality. Lipopolysaccharide decreased cytochromes P-450 concentrations and activities to similar extents at all time points tested in both control and 3,3′,4,4′-tetrabromobiphenyl-treated rats. In conclusion, 3,3′,4,4′-tetrabromobiphenyl treatment increases the amount of tumor necrosis factor released into the serum after lipopolysaccharide exposure and sensitizes animals to lipopolysaccharide hepatotoxicity and lethality 1 to 2 days after 3,3′,4,4′-tetrabromobiphenyl administration. However, the enhancement of endotoxicity does not correlate with increased serum tumor necrosis factor or altered activities of cytochromes P-450. (HEPATOLOGY 1991;14:1201–1208.)