Background and Purpose -The paraoxonases are involved in protecting low-density lipoprotein (LDL) from lipid oxidation. Paraoxonase 1 (PON1) was implicated in susceptibility to coronary artery disease and stroke in previous studies. We evaluated, in a comprehensive way, all 3 paraoxonase genes for association with stroke observed in the Cholesterol and Recurrent Events (CARE) trial. Methods - Over 2500 subjects enrolled in the CARE trial were genotyped for 14 single nucleotide polymorphisms, including 7 newly identified in this study, in the 3 paraox onase genes. Results -A glutamine (Gln)/arginine (Arg) polymorphism at amino ac id residue 192 in PON1 was significantly associated with stroke (P=0.003 in mult ivariate analysis, including age, sex, LDL, hypertension, diabetes, smoking, and pravastatin treatment as covariates). The odds ratios were 2.28 (95%CI, 1.38 t o 3.79) for Gln/Arg heterozygotes and 2.47 (95%CI, 1.18 to 5.19) for Arg/Arg ho mozygotes compared with Gln/Gln homozygotes. These results are consistent with 2 of 3 other published studies. In combined analysis of all 4 studies, the associ ation between Gln192Arg SNP and stroke was highly significant (χ28df=45.58, P < 0.000001). Sequence analysis of the PONl gene from seventy stroke cases reveale d a novel nonsense mutation at codon 32 in one stroke case, which was not detect ed in over 2500 unaffected individuals. Polymorphisms in the PON2 and PON3 genes were not associated with stroke. Conclusions -These results suggest that Gln19 2Arg genotype is an important risk factor for stroke. Background and Purpose-The paraoxonases are involved in protecting low-density lipoprotein (LDL) from lipid oxidation. Paraoxonase 1 (PON1) was implicated in susceptibility to coronary artery disease and stroke in previous studies. We evaluated, in a comprehensive way, all 3 Methods - Over 2500 subjects enrolled in the CARE trial were genotyped for 14 single nucleotide polymorphisms, including 7 newly identified in this study, in the 3 paraox onase genes Results -A glutamine (Gln) / arginine (Arg) polymorphism at aminoacid residue 192 in PON1 was significantly associated with stroke (P = 0.003 in mult ivariate analysis, including age, sex, LDL, hypertension, diabetes, smoking, and The odds ratios were 2.28 (95% CI, 1.38 to 3.79) for Gln / Arg heterozygotes and 2.47 (95% CI, 1.18 to 5.19) for Arg / Arg ho mozygotes compared with Gln / Gln homozygote s. The combined analysis of all 4 studies, the associative relationship between Gln192Arg SNP and stroke was highly significant (χ28df = 45.58, P <0.000001). Sequence analysis of the PON1 gene from Seventy stroke cases reveale da novel nonsense mutation at codon 32 in one stroke case, which was not detect ed in over 2500 unaffected individuals. Polymorphisms in the PON2 and PON3 genes were not associated with stroke. Conclusions-These results suggest that Gln19 2Arg genotype is an important risk factor for stroke.