Although moderate alcohol consumption is associated with a lower risk of cardiovascular disease (CVD), little is known of the effects of alcohol dehydrogenase 1C (ADH1C) polymorphism on the association between alcohol and CVD. We used data on 1,805 unrelated subjects in the Framingham Offspring Study to assess whether rs1693482 and rs698, 2 single nucleotide polymorphisms of the ADH1C gene, modify the relation between alcohol consumption and prevalent CVD. The 2 single nucleotide polymorphisms were in linkage disequilibrium (D' = 0.99, R(2) = 0.96). There was evidence for a U-shaped association between alcohol consumption and CVD in this population. Multivariable adjusted odds ratios for prevalent CVD were 0.63 (95% confidence interval 0.41 to 0.97) and 0.80 (95% confidence interval 0.46 to 1.41) for CT and TT genotypes of rs1693482 relative to CC genotype (model p <0.0001). Corresponding values for AG and GG genotypes of rs698 were 0.68 (95% confidence interval 0.45 to 1.04) and 0.84 (95% confidence interval 0.49 to 1.46), respectively, compared with the AA genotype (model p <0.0001). There were nonstatistically significant associations between rs693482 C-->T and rs698 A-->G mutations and prevalent CVD among current drinkers (lower CVD prevalence with minor allele) but not among nondrinkers in whom the minor allele was associated with a trend toward higher CVD prevalence (p values for interaction are 0.16 for rs1693482 and 0.52 for rs698). Alcohol consumption was associated with high-density lipoprotein cholesterol across all genotypes of the 2 single nucleotide polymorphisms in a dose-response fashion without evidence for interaction. In conclusion, these data suggest borderline interactions between genes and environment of ADH1C variation and alcohol intake on prevalent CVD. The interaction does not appear to be mediated through effects on high-density lipoprotein cholesterol.