Arylamine N-acetyltransferase 2 (NAT2) is involved in both the detoxification and bioactivation of carcinogenic arylamines and other mutagens. This enzyme is polymorphic, and the fast and slow phenotypes are thought to be risk factors for colon and bladder cancer, respectively. Here, we report on a case-control study of adenomatous and hyperplastic polyps, with particular attention to tobacco smoking, a known risk factor for adenomas, and polymorphisms of NAT2. All participants underwent complete colonoscopy and were subsequently divided into case and control groups on the basis of pathology. Cases were diagnosed with confirmed adenomas (n = 527) or hyperplastic polyps (n = 200); controls (n = 633) had no history of colonic neoplasia and no polyps at colonoscopy. NAT2 genotype was determined using an oligonucleotide ligation assay and fast, intermediate, or slow phenotype imputed. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals were computed using logistic regression adjusting for age, sex, nonsteroidal anti-inflammatory drug use, and hormone replacement therapy use. Smoking was associated with an increased risk of adenomas [current versus never smoking OR = 2.0 (95% confidence interval, 1.4-2.9)] and hyperplastic polyps [current versus never smoking OR = 4.1 (2.6-6.5)]. NAT2 status among adenomatous polyp patients and hyperplastic polyp patients, respectively, showed ORs of 1.1 (0.8-1.4) and 1.2 (0.8-1.6; intermediate versus slow) and 1.1 (0.6-1.9) and 0.9 (0.4-1.9; fast versus slow). There were no differences in risk when adenoma patients were stratified on multiplicity, size, or histopathological subtype of polyps. Never-smokers showed no variation in risk across acetylator status for either species of polyp, whereas current smokers showed ORs of 2.0 (1.2-3.2) and 2.3 (1.4-3.9) for adenomas and 3.9 (2.1-7.1) and 4.9 (2.6-9.4) for hyperplastic polyps for slow and intermediate/fast NAT2, respectively, compared with slow-NAT2 never-smokers. Risks of both multiple [OR = 4.3 (2.1-8.8)] and large [OR = 3.8 (1.9-7.5)] adenomas were somewhat elevated in current smokers with an intermediate/fast phenotype compared with smokers with a slow NAT2 phenotype, but the interaction was not statistically significant. Risk of hyperplastic polyps and adenomatous polyps is strongly related to smoking. There is little suggestion of interaction between NAT2 status and smoking and no relationship with NAT2 genotype alone.