Antipyrine total clearance and the formation clearance of its major metabolites were studied in normal, healthy male volunteers before and after multiple dosing for approximately three weeks with phenytoin (six subjects) and carbamazepine (six subjects). Total antipyrine clearance increased on average by 91% after phenytoin dosing and by 61% after carbamazepine and individual increases correlated well with mean plasma concentrations of the anti-epileptic drug. The increase in total clearance resulted largely from increased formation clearances of the 4-hydroxy and 3-hydroxymethylantipyrine metabolites with minimal effect on the norantipyrine pathway, following treatment with both enzyme-inducing drugs. It is concluded that both phenytoin and carbamazepine have similar effects on antipyrine metabolism and that these effects are mediated by induction of specific forms of cytochrome P450.