The 4'-hydroxylation of S-mephenytoin is polymorphic in man. The poor metabolizer (PM) phenotype exhibits a lower frequency in Caucasians (2-5%) compared to Oriental populations (13-23%). Previous studies from our laboratory have described two mutations (CYP2C19m1 and CYP2C19m2) which account for approximately 100% of Oriental and approximately 85% of Caucasian PM alleles. The present study examined whether the genotype predicted the phenotype in Japanese, Filipino and Saudi Arabian populations, and compared the frequencies of the defective CYP2C19 alleles in these populations with those found in European-Americans, Chinese-Taiwanese, and African-Americans from North Carolina. Among 53 Japanese, 15% were PMs and among 52 Filipinos 23% were PMs. Among 97 Saudi Arabians, only two were PMs. There was a complete concordance between genotype and phenotype in all three populations. The incidence of CYP2C19m1 was 0.23 (95% confidence limits 0.15-0.31) in Japanese, 0.39 (95% confidence limits 0.29-0.48) in Filipinos, 0.32 (95% confidence limits 0.26-0.38) in Chinese-Taiwanese, 0.15 (95% confidence limits 0.10-0.20) in Saudi Arabians, 0.13 (95% confidence limits 0.08-0.17) in European-Americans, and 0.25 in African-Americans from North Carolina (95% confidence limits (0.14-0.31). The incidence of CYP2C19m1 in Saudi Arabians was similar to that found in European-Americans, and significantly lower than that found in Oriental populations or African-Americans (p < 0.05). CYP2C19m2 was not found in European-Americans, Saudi Arabians or African-Americans (95% confidence limits 0-0.014). The incidence of CYP2C19m2 in the three Oriental populations ranged from 0.10 (95% confidence limits 0.05-0.17) in Japanese and 0.08 (95% confidence limits 0.03-0.13) in Filipinos to 0.06 (95% confidence limits 0.03-0.08) in Chinese-Taiwanese.