Recent studies have implicated paraoxonase, an HDL-associated enzyme, in providing protection against LDL oxidation, thus affecting the risk of coronary heart disease (CHD) in the general population. In this study, we evaluated the distribution of a biallelic PON polymorphism at codon 192 (A and B alleles) and its relationship with plasma lipids and CHD in two racial groups comprising Asian Indians and Chinese from Singapore. The frequency of the B allele was significantly higher in Chinese control subjects than in Indian control subjects (0.58 versus 0.33; P < .0001). With the exception of a marginal effect on apolipoprotein A-I levels in Indians, no other significant association was observed between the PON polymorphism and quantitative lipid traits in either racial group. However, there was a race-specific association of the B allele with CHD in Indians but not in Chinese. The Indian CHD patients had a significantly higher frequency of the B allele than control subjects (.43 versus .33; P = .014). The age- and sex-adjusted odds ratio for developing CHD with the B allele (BB+AB genotypes) was 2.01 (95% CI, 1.17 to 3.45; P = .011) compared with the A allele (AA genotype). When the Indian patients were stratified into subgroups, the association remained significant in nondiabetic patients (odds ratio, 2.29; P = .008), and it became stronger in patients with myocardial infarction (odds ratio, 2.94; P = .004) than in patients without myocardial infarction (odds ratio, 1.11; P = .76). These data indicate that a common polymorphism in the PON gene is an independent risk factor for CHD in populations with white ancestry.