Erythromycin has been reported to interact with the anticonvulsant, carbamazepine, in both children and adults. Toxic serum levels of carbamazepine are observed within 24 h of antibiotic administration, suggesting a mechanism not previously described for other erythromycin-based drug interactions. In rats erythromycin significantly depressed the elimination of carbamazepine in animals induced with carbamazepine for 4 days but had no effect on carbamazepine elimination in noninduced animals. Although the in vitro metabolism of carbamazepine to its epoxide by hepatic microsomes prepared from noninduced rats was significantly inhibited by erythromycin, the inhibition of carbamazepine epoxidation was greatly enhanced in carbamazepine-induced rats. In the pig the sensitivity of carbamazepine metabolism to erythromycin was much greater than in the rat, indicating the existence of a large species difference in this particular drug interaction. It is concluded that the interaction between erythromycin and carbamazepine is caused by a direct inhibition of carbamazepine oxidation by the antibiotic.