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Carlos Eduardo Silvado,1 Vera Cristina Terra,1 Carlos Alexandre Twardowschy2 1Comprehensive Epilepsy Program, Hospital de Clinicas, Federal University of Parana (UFPR), Curitiba, Brazil; 2Department of Neurology, Catholic University of Parana (PUCPR), Curitiba, Brazil Abstract: Phenytoin (PHT) is an antiepileptic drug widely used in the treatment of focal epilepsy and status epilepticus, and effective in controlling focal seizures with and without tonic–clonic generalization and status epilepticus. The metabolization of PHT is carried out by two oxidative cytochrome P450 enzymes CYP2C9 and CYP2C19; 90% of this metabolization is done by CYP2C9 and the remaining 10% by CYP2C19. Genetic polymorphism of CYP2C9 may reduce the metabolism of PHT by 25–50% in patients with variants *2 and *3 compared to those with wild-type variant *1. The frequency distribution of CYP2C9 polymorphism alleles in patients with epilepsy around the world ranges from 4.5 to 13.6%, being less frequent in African-Americans and Asians. PHT has a narrow therapeutic range and a nonlinear pharmacokinetic profile; hence, its poor metabolization has significant clinical implications as it causes more frequent and more serious adverse effects requiring discontinuation of treatment, even if it had been effective. There is evidence that polymorphisms of CYP2C9 and the use of PHT are associated with an increase in the frequency of some side effects, such as cerebellar atrophy, gingival hypertrophy or acute cutaneous reactions. The presence of HLA-B*15:02 and CYP2C9 *2 or *3 in the same patient increases the risk of Stevens–Johnson syndrome and toxic epidermal necrolysis; hence, PHT should not be prescribed in these patients. In patients with CYP2C9 *1/*2 or *1/*3 alleles (intermediate metabolizers), the usual PHT maintenance dose (5–10 mg/kg/day) must be reduced by 25%, and in those with CYP2C9 *2/*2, *2/*3 or *3/*3 alleles (poor metabolizers), the dose must be reduc