Genetic variability in DNA repair genes may contribute to differences in DNA repair capacity and susceptibility to cancer, especially in the presence of exposures such as smoking. In a Minnesota-based case-control study of cases with only adenomatous polyps (n = 384), only hyperplastic polyps (n = 191), or both types of polyps (n = 119) versus polyp-free controls (n = 601), we investigated the role of polymorphisms in the DNA repair genes O(6)-methylguanine methyltransferase (MGMT; p.L84F and p.I143V), XPD (p.D312N and p.K751Q), and XPG (p.D1104H). MGMT polymorphisms were not associated with polyp risk. Overall, a homozygous variant XPD-combined genotype was associated with an increased risk of adenomatous polyps [odds ratio (OR), 1.57; 95% confidence interval (95% CI), 1.04-2.38] and an XPGHH1104 genotype with a decreased risk of hyperplastic polyps (OR, 0.36; 95% CI, 0.13-0.98). However, age stratification showed that the XPD association was present only in subjects >/=60 years old (OR, 3.77; 95% CI, 1.94-7.35), whereas the XPG association was observed largely in subjects <60 years old (OR, 0.20; 95% CI, 0.05-0.91). Smokers did not have a significantly increased risk of adenomatous polyps in the absence of synchronous hyperplastic polyps, except for subjects with a homozygous variant XPD genotype or a homozygous wild-type XPG genotype (OR, 3.93; 95% CI, 1.68-9.21 and OR, 1.59; 95% CI, 1.01-2.50, respectively). Smoking was associated with a statistically significant 2.5- to 6-fold increased risk of hyperplastic polyps for individuals with most of the DNA repair genotypes. However, no substantial increase was observed among individuals who were homozygous variant for XPG (1104HH; OR, 1.38; 95% CI, 0.25-7.65). Our data suggest that polymorphisms in DNA repair genes may be risk factors for colorectal neoplasia and that they may exacerbate the effects of exposures to carcinogens.