We examined the effect of CYP2C9/19 polymorphisms on the pharmacokinetics of phenytoin in 17 Japanese patients with epilepsy. The maximal elimination rate (V_max) of phenytoin was slightly decreased (up to 14%) in patients with CYP2C19 mutations for the defective allele. The V_max values in patients with a CYP2C9 mutation for the heterozygous Ile/Leu³⁵⁹ allele were 40% lower than those in patients with wild-type CYP2C9 for the homozygous Ile³⁵⁹ allele. These findings suggested that the genetic polymorphism of CYP2C isoenzymes plays an important role in the pharmacokinetic variability of phenytoin, and that the mutation in CYP2C9 proteins is a determinant of impaired metabolism of the drug.