Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor superfamily initially shown to be a key regulator of fat cell differentiation, can inhibit cell growth and induce apoptosis in colon cell lines. There are heterozygous loss of function mutations in the gene encoding PPARgamma in tumors from approximately 10% of human colon cancer patients. A common structural polymorphism has been detected in the PPARgamma gene at codon 12 (Pro12Ala). We investigated the hypothesis that the PPARgamma Pro12Ala polymorphism is associated with colorectal adenoma risk in a recently concluded case-control study of incident sporadic colorectal adenomas (163 cases and 212 controls). The multivariate-adjusted odds ratio (OR) for incident sporadic colorectal adenoma was 0.65 (95% CI 0.39-1.09) for those with the Pro12Ala or Ala12Ala genotype compared with those with the Pro12Pro genotype. Multivariate-adjusted inverse associations with the Ala12 variant were more pronounced among those who were female (OR 0.36, 95% CI 0.18-0.75) or did not take non-steroidal anti-inflammatory drugs (OR 0.38, 95% CI 0.14-1.00). Marginally significant results were observed among those with a lower waist:hip ratio (OR 0.52, 95% CI 0.24-1.12) or a lower body mass index (OR 0.46, 95% 0.20-1.05). Smoking was a very strong risk factor (OR 2.34, 95%CI 1.37-4.02) for colorectal adenoma among those with the wild-type (Pro12Ala) genotype, but not those with the Ala12 variant (OR 0.86, 95%CI 0.35-2.09). Larger studies are needed to validate these results, which suggest that the PPARgamma Pro12Ala polymorphism may interact with other factors to protect against colorectal adenoma.