Recent reports have suggested that polymorphisms in the human paraoxonase (HUMPONA) gene may be a genetic risk factor for coronary artery disease (CAD) in white populations. However, this association has not yet been confirmed in other ethnic populations. We studied 75 Japanese patients with CAD, whose coronary lesions were confirmed by angiography, and 115 Japanese control subjects with no history of CAD and a normal resting electrocardiogram. The assays for genotyping the two polymorphisms in the HUMPONA gene (192Arg/Gln and 55Leu/Met) were based on changes in restriction enzyme digestion patterns. For codon 192, the frequencies of the Arg-coding allele (B allele) in both patients and control subjects were much higher than those from published results of whites (.26 to .31), and the difference between patients (.74) and control subjects (.59) was statistically significant (P = .002). The patient group had a higher proportion of Arg/Arg (B/B) homozygotes (52.0% vs 32.2%, P = .006). For codon 55, the frequencies of the Leu-coding allele in control subjects and patients were much higher (.91 and .93, respectively) than those published results for whites, but there was no difference between Japanese control subjects and Japanese patients. When subjects with the 55Leu/Leu genotype only were analyzed, 192Arg/Arg homozygotes were still significantly more frequent in the patients than in the control subjects (55.4% vs 37.2%, P = .024), and the frequency of the 192Arg allele was also higher in patients than control subjects (P = .013). Logistic regression analysis including conventional coronary risk factors revealed that 192Arg is an independent risk factor for CAD. Thus, in the Japanese, the association of CAD with the 192Arg variant of HUMPONA (B-type enzyme) is similar to that reported for whites, although the allele frequencies for 192Arg and 55Leu are much higher in the former than the latter population.