The authors investigated the impact of theCYP2D6genotype on steady-state concentrations of nortriptyline (NT) and its metabolites,trans-10-hydroxynortriptyline (EHNT) andcis-10-hydroxynortriptyline in a Japanese population of psychiatric patients. Forty-one patients (20 men and 21 women) were orally administered nortriptyline hydrochloride. The allele frequencies of theCYP2D6*5andCYP2D6*10were 4.9% and 34.1%, respectively. Significant differences in NT concentrations corrected for dose and weight were observed between the subjects with no mutated alleles and those with one mutated allele (mean ± SD for no mutated alleles vs. one mutated allele: 70.3 ± 25.4 vs. 98.4 ± 36.6 ng/mL·mg−1·kg−1;t= 2.54,df= 33,p< 0.05) and between the subjects with no mutated alleles and two mutated alleles (no mutated alleles vs. two mutated alleles: 70.3 ± 25.4 vs. 147 ± 31.1 ng/mL·mg−1·kg−1;t= 5.87,df= 19,p< 0.0001). Also, a significant difference in the NT/EHNT ratio, which is representative of the hydroxylation ratio of NT, was observed between the subjects with no mutated alleles and those with two mutated alleles (no mutated alleles vs. two mutated alleles: 0.82 ± 0.30 vs. 2.71 ± 0.84;t= 7.86,df= 19,p< 0.0001). Multiple regression analysis showed that the number of mutated alleles ofCYP2D6,which was the only significant factor, accounted for 41% and 48% of the variability in log(NT corrected for dose and weight) and log(NT/EHNT), respectively.