Alcohol consumption at moderate levels has been associated with decreased risk of coronary heart disease (CHD). However, the cardio-protective effect of alcohol may be restricted to subjects with a particular genotype of the cholesterol ester transfer protein (CETP) polymorphism. There is evidence for this from one study in men, but the finding has not been confirmed since. The present study specifically re-examines the potential modification of the association between alcohol consumption and CHD by the CETP TaqIB (rs708272) polymorphism in a sample including both men and women. The INTERGENE case-control study consists of 618 patients with CHD and 2921 control subjects, of whom 19% were homozygous for the CETP TaqIB B2 allele. Alcohol consumption was categorized into sex-specific tertiles of ethanol intake, with non-drinkers constituting a separate category. Logistic regression was used to determine the association between CHD with genotype, ethanol intake, and their interaction. Participants with intermediate ethanol intake (2nd tertile) had lower risk of CHD than those with low ethanol intake (OR = 0.65; 95% CI 0.50–0.85). The strongest protective association was seen in theCETP TaqIB B2 homozygotes for intermediate vs. low ethanol intake (odds ratio [OR] = 0.21; 95% confidence interval [CI] 0.10–0.44). The interaction between ethanol intake and genotype was statistically significant (p = 0.008), and of similar size in men and women though significant only in men (p = 0.01). The effect modification could not be explained by differences in lifestyle, socioeconomics, or alcohol-related biological variables such as HDL-cholesterol. Our study is the first to replicate previous findings of an effect modification in men. It gives only suggestive results for women, possibly due to the small number of female cases (n = 165). The prevented fraction for the favorable combination of genotype and alcohol consumption is about 6%, a value suggesting that the cardio-protective effect of moderate alcohol consumption applies only to a small segment of the general population.