Recent studies have suggested that hyperplastic polyps may be benign precursor lesions for a distinct subset of colorectal tumors. We conducted a clinic-based case-control study to evaluate risk factors for hyperplastic polyps. Cases with hyperplastic polyps (n = 219), adenomas (n = 437), and both types of polyps (n = 138), along with colonoscopy-negative controls (n = 708), were identified at a gastroenterology practice in the Minneapolis area during 1991-1994. A self-administered questionnaire was used to collect risk factor information. Risk factors for hyperplastic and adenomatous polyps were generally similar to those for colorectal cancer. Male sex, smoking, and alcohol consumption were associated with increased risk of all polyp groups; nonsteroidal anti-inflammatory drug use, hormone replacement therapy use, and calcium intake were associated with reduced risk. There was no apparent association between increasing age and hyperplastic polyp risk (P = 0.21) in this analysis, although it was a strong risk factor for adenoma (P < 0.001). The odds ratio (OR) for hyperplastic polyps associated with >25 pack-years of smoking was 4.1 [95% confidence interval (CI), 2.2-7.6], whereas the OR for adenoma alone was 1.3 (95% CI, 0.8-2.3). The OR estimate for individuals diagnosed with both polyp types was 4.2 (95% CI, 1.9-9.3). These results suggest, as one possibility, that the consistent association of adenoma and smoking observed in previous studies may be partially attributable to the inclusion of individuals with both adenomas and hyperplastic polyps in the adenoma case group. To the contrary, individuals with both polyp types may be expressing a phenotype distinct from those who have only adenomas and should be considered separately. Further studies are necessary to establish which polyp phenotypes are related to smoking. Overall, the similarity of the risk profiles of colorectal hyperplastic polyps, adenoma, and cancer provides additional support for the growing body of evidence that some hyperplastic polyps may have neoplastic potential.