It has been shown that risperidone (+)-9-hydroxylation is enantioselectively catalyzed by the polymorphic CYP2D6 in human liver. This study aimed to examine the effect of CYP2D6 genotype on (+)-9-hydroxylation of risperidone in schizophrenic patients. Subjects were 38 Japanese schizophrenic inpatients receiving 6 mg/day of risperidone. Plasma concentrations of risperidone and (+)- and (-)-9-hydroxyrisperidone at steady state were quantified using LC/MS/MS and HPLC with alpha 1 acid-AGP chiral column, respectively. The CYP2D6*5(*5) and *10 alleles were identified using polymerase chain reaction (PCR) methods. Twenty patients had no mutated allele, 14 had one mutated allele, and 4 had two mutated alleles. There were significant differences in the steady-state plasma concentrations of risperidone (ANOVA; p < 0.0001) among the three genotype groups, while the CYP2D6 genotype did not affect the steady-state plasma concentrations of (+)-9-hydroxyrisperidone (p = 0.314) or (-)-9-hydroxyrisperidone (p = 0.957). The concentration ratio of risperidone to 9-hydroxyrisperidone was strongly dependent on the CYP2D6 genotypes. This study suggests that CYP2D6 activity strongly influences the steady-state plasma concentrations of risperidone and risperidone/9-hydroxyrisperidone concentration ratios but is unlikely to determine enantio-selectivity in the steady-state plasma concentrations of 9-hydroxyrisperidone in the clinical situation.