The purpose of this study was to evaluate the influence of cimetidine on carbamazepine pharmacokinetics in healthy adults, since carbamazepine toxicity in a patient has been attributed to an interaction with cimetidine and in vitro and in vivo studies in rats have shown that cimetidine inhibits carbamazepine metabolism. Eight healthy volunteers received a single 600-mg oral dose of carbamazepine on two occasions, separated by 1 month. In a randomized crossover sequence, cimetidine 1,200 mg/day or placebo was taken for 48 h before and continuing for 7 days after each carbamazepine dose. Plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide and urine concentrations of carbamazepine, the 10,11-epoxide, and the transdiol metabolite were measured in samples collected for 154 h following each carbamazepine dose. Cimetidine treatment was associated with increases of 26 and 18% in carbamazepine area under the concentration-time curve (AUC) and elimination half-life, respectively. There was also an increase in carbamazepine-10,11-epoxide AUC (27%) and t 1/2 (12%) during cimetidine treatment. There was no difference in the ratio of the 10,11-epoxide to the carbamazepine AUC between treatments. The urinary excretion (expressed as molar percentage of the administered dose) of carbamazepine, 10,11-epoxide, and transdiol metabolite all increased with cimetidine. Although cimetidine appears to inhibit carbamazepine elimination based on the increased elimination half-life, the effect must be on carbamazepine metabolic pathways that we could not measure and that account for greater than 80% of the administered dose. The clinical significance of this interaction should be verified under steady-state conditions when carbamazepine autoinduction is present.