We examined the effect of CYP2C9/19 polymorphisms on the pharmacokinetics of phenytoin in 17 Japanese patients with epilepsy. The maximal elimination rate (Vmax) of phenytoin was slightly decreased (up to 14%) in patients with CYP2C19 mutations for the defective allele. The Vmax 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.