Xeroderma pigmentosum complementation group C (XPC) is responsible for DNA damage recognition in the initial steps of the nucleotide excision repair pathway. Genetic variations in the XPC gene may be associated with impaired protein function and increased risk for bladder cancer. To elucidate the roles of common polymorphisms of XPC in the etiology of bladder cancer, we conducted a hospital-based case-control study including 578 Caucasian incident bladder cancer patients and 578 age- and gender-matched Caucasian controls. We analyzed the associations of the genotypes, haplotypes and diplotypes of three XPC polymorphisms, Ala499Val (C-->T), PAT (-/+) and Lys939Gln (A-->C), with the risk of bladder cancer. No significant association was found for any individual polymorphism. However, the C-C and T-A (indicated as in the order of Ala499Val-PAT-Lys939Gln) haplotypes were associated with reduced bladder cancer risks, with odds ratios (ORs) of 0.51 [95% confidence interval (CI) = 0.34-0.78] and 0.79 (0.60-1.04), respectively. The protective effects were more evident in men, people younger than 59 years, and ever-smokers. We also found that four diplotypes were significantly associated with reduced bladder cancer risk, with ORs (and 95% CIs) of 0.53 (0.34-0.82) for C-A/T-A, 0.48 (0.27-0.84) for C-A/C-C, 0.18 (0.053-0.60) for C-C/C-C and 0.57 (0.36-0.90) for C+C/C+C. These results suggest that sequence variants in the XPC gene might modulate the risk of bladder cancer.