Acetaminophen metabolism and clearance after a single 1 gm oral dose of the drug was investigated in 12 healthy men, six of whom were cigarette smokers, and in six men who were receiving anticonvulsant drugs for epilepsy. The 12 healthy subjects were studied before and after 1 wk of pretreatment with cimetidine (1 gm/day) or sulfinpyrazone (800 mg/day). There was no significant difference in acetaminophen clearance (ClAP) between nonsmokers and smokers; cimetidine pretreatment had no effect on ClAP. Neither cigarette smoking nor cimetidine pretreatment had a significant effect on any of the metabolic pathways of acetaminophen. In contrast, sulfinpyrazone pretreatment increased ClAP by 23% (from 5.70 ± 0.21 to 7.00 ± 0.39 ml/min/kg) and ClAP was 46% greater in the epileptic subjects who received anticonvulsant drugs than in the control group (8.32 ± 0.45 and 5.70 ± 0.21 ml/ml/kg). In both cases the increase in ClAP was a result of induction of acetaminophen glucuronidation and oxidation; clearance of the glucuronic acid conjugate was 26% and 59% greater and clearance of the glutathione-derived conjugates (reflecting the activity of the oxidative pathway) was 43% and 60% greater in the groups given sulfinpyrazone and anticonvulsants, respectively.