Previous studies have suggested that certain genetic polymorphisms, specifically the Xeroderma pigmentosum group D (XPD) gene codon 751 and the X-ray repair cross-complementing group 1 (XRCC1) gene codon 399 polymorphisms, were associated with an increased risk of lung cancer, and, in some studies, with a greater risk for mutations in the p53 tumor suppressor gene in lung tumors. To evaluate whether these gene polymorphisms may be associated with an increased risk for bladder cancer or in association with p53 mutation status in bladder tumors, we screened for polymorphisms at XPD codons 751 and XRCC1 codon 399 in DNA isolated from blood of 194 bladder cancer patients and 313 healthy controls and for mutations in exons 4 to 8 of the p53 gene in bladder tumor DNA from 174 bladder cancer patients. There was a significantly higher prevalence of the XPD 751 Gln allele among the bladder cancer group, compared with the control group. No association was found between bladder cancer risk and the XRCC1 399 polymorphism. p53 mutations were found in 20.1% (35/174) patients. There was no difference in p53 mutation status among individuals with different genotypes. These results suggest that individuals who have the XPD 751 Gln allele may be at an increased risk for bladder cancer, although this may not lead to an increased risk for mutations in the p53 gene.