The effect of both concomitant administration and pretreatment with isoniazid on the activity of the hepatic drug-metabolizing enzymes of healthy young volunteers, as indicated by the antipyrine clearance test, is reported. Concomitant administration of isoniazid with antipyrine results in a significant decrease in the hepatic clearance of the latter compound. In contrast, pretreatment for 14 days with isoniazid had no effect on antipyrine elimination kinetics. It is concluded that isoniazid depresses hepatic drug metabolism only when present in significant amounts at the hepatic site of drug oxidation.