Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated nuclear receptor that plays a key role in adipogenesis and adipocyte gene expression, and has recently been linked with possible antineoplastic effects in colonic carcinogenesis. PPARgamma2 and gamma3 are two transcripts arising from the PPARgamma gene through differential promoter usage and alternative splicing. We investigated the associations between PPARgamma2 Pro12Ala and PPARgamma3 C-681G gene polymorphisms and colorectal cancer (CRC) risk in a case-control study nested within the Singapore Chinese Health Study. Genotypes for the PPARgamma2 and PPARgamma3 polymorphisms were determined on 362 incident CRC cases and 1164 cohort controls by direct sequencing and by fluorogenic 5'-nuclease assay. Unconditional logistic regression models were used for statistical analyses. With adjustment for CRC risk factors, subjects with one or two copies of the G allele of the PPARgamma2 Pro12Ala polymorphism showed a statistically significant reduction in risk compared to those with the CC genotype [odds ratio (OR)=0.53, 95% confidence interval (CI)=0.30-0.92]. For the PPARgamma3 C-681G polymorphism, subjects with one or two copies of the C allele showed a reduction in risk compared to those with the GG genotype (OR=0.72, 95% CI=0.51-1.04). When PPARgamma2 and PPARgamma3 genotypes were considered simultaneously, the number of putative low-risk genotypes was significantly associated with reduced risk of CRC in a gene-dose-dependent manner; the OR (95% CI) was 0.72 (0.49-1.07) among subjects possessing one low-risk genotype (either PPARgamma2 or PPARgamma3), and the comparable figure among subjects possessing both low-risk genotypes was 0.19 (0.07-0.51).