Male F344 rats were exposed either to 1.87 mg/L (600 ppm) carbon disulfide (CS2) for 6 hr/day by inhalation for 1, 2, or 3 consecutive days, or to 0.1% phenobarbital (PB) in the drinking water starting 5 days before exposure to CS2, or to both. Combined treatments (CS2 + PB) resulted in a decrease in hepatic cholesterol synthesis, increases in hepatic cholesterol concentration and relative liver weight, and histopathologic damage. Maximal inhibition of cholesterol synthesis was observed following 1 day of combined treatments, while the increases in hepatic cholesterol concentration were similar following 1, 2, or 3 days of combined treatments. Exposure to CS2 only produced a pattern of inhibition of cholesterol synthesis that was similar to, though less extensive than, that seen following combined treatments. All reported alterations caused by combined treatments of CS2 + PB were reversible; recovery was, in all cases, essentially complete by day 11 after a single exposure to 1.87 mg/L CS2. With the exception of cholesterol concentration where time to recovery was decreased by continuation of PB, the time required for recovery from the effects of combined treatments of CS2 + PB was not affected by whether or not PB was continued after CS2 exposure. The reported observations support the theory that metabolism of CS2 is involved in the expression of CS2-mediated alterations of hepatic cholesterol metabolism.