Cigarette smoking has been associated inconsistently with colon cancer. The extent to which genetic profile influences susceptibility to the inducement of colon cancer by cigarette smoking is not known. In this study, we evaluated the associations between smoking cigarettes and polymorphisms of the NAT2 and GSTM-1 genes using data obtained from an incident case-control study of 1993 cases of colon cancer and 2410 age- and sex- matched controls. Neither NAT2 nor GSTM-1 polymorphisms were significantly associated with colon cancer, except among older women, in whom the intermediate/rapid imputed phenotype was associated with increased risk of colon cancer [odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.0-1.81. Using several indicators of cigarette smoking, we observed no significant interaction between these genotypes and cigarette smoking and colon cancer. The major variation in association with colon cancer was from the amount of cigarette exposure, with those smoking a pack or more of cigarettes per day being at an approximately 40% increased risk of colon cancer; this association did not vary by genotype. However, those who stopped smoking 5-14 years prior to diagnosis and who where intermediate/rapid acetylators were at a slightly greater risk than those who were slow acetylators (for men, OR = 1.6, 95% CI = 1.0-2.4; for women, OR = 2.5, 95% CI = 1.4-4.4). Associations were similar when proximal and distal tumors were examined and separated for age at the time of diagnosis. The lack of an association does not rule out the possibility of other genetic polymorphisms interacting with cigarette smoke to cause colon cancer, nor does it take into account individual phenotypic variability.