The polymorphic gene NAT2 is a major determinant of N-acetyltransferase activity and, thus, may be responsible for differences in one's ability to bioactivate heterocyclic amines, a class of procarcinogens in cooked meat. An unusually marked geographic variation in enzyme activity has been described for NAT2. The present study re-examines the international direct correlation reported for meat intake and colorectal cancer (CRC) incidence, and evaluates the potential modifying effects of NAT2 phenotype and other lifestyle factors on this correlation. Country-specific CRC incidence data, per capita consumption data for meat and other dietary factors, prevalence of the rapid/intermediate NAT2 phenotype, and prevalence of smoking for 27 countries were used. Multiple linear regression models were fit and partial correlation coefficients (PCCs) were computed for men and women separately. Inclusion of the rapid/intermediate NAT2 phenotype with meat consumption improved the fit of the regression model for CRC incidence in both sexes (males-R (2) = 0.78, compared to 0.70 for meat alone; p for difference in model fit-0.009; females-R (2) = 0.76 compared to 0.69 for meat alone; p = 0.02). Vegetable consumption (inversely and in both sexes) and fish consumption (directly and in men only) were also weakly correlated with CRC, whereas smoking prevalence and alcohol consumption had no effects on the models. The PCC between NAT2 and CRC incidence was 0.46 in males and 0.48 in females when meat consumption was included in the model, compared to 0.14 and 0.15, respectively, when it was not. These data suggest that, in combination with meat intake, some proportion of the international variability in CRC incidence may be attributable to genetic susceptibility to heterocyclic amines, as determined by NAT2 genotype.