Xeroderma pigmentosum group F (XPF) has an essential role in the nucleotide excision repair pathway that removes a wide variety of DNA lesions. We hypothesized that genetic variants in XPF are associated with bladder cancer risk and recurrence. We selected three tagging single nucleotide polymorphisms (tagSNPs) from the HapMap database for the Chinese and genotyped them in a two-stage case-control study to evaluate the association and further examined the functionality of a novel polymorphism in the promoter. The two-stage analysis found that the rs744154 tagSNP in the XPF intron 1, which was linkage disequilibrium with the -357A>C polymorphism in the promoter region, was associated with a protective effect on bladder cancer risk. Electrophoretic mobility shift assay (EMSA) further revealed that the -357C allele decreased the binding ability of transcriptional factors to the XPF promoter. The vector construct containing the -357C allele had a lower luciferase expression than did the -357A allele. The -357C allele in the transcription factor-binding site was also associated with decreased expression levels of both XPF mRNA and protein in bladder cancer tissues. Furthermore, patients with the -357C allele had a shorter overall recurrence-free survival than did patients with the -357A allele. Our results suggest that the XPF promoter -357A>C polymorphism may regulate the expression of XPF and thereby contribute to susceptibility to and prognosis of bladder cancer. Further larger studies with different populations are warranted to confirm these findings.