Reduced DNA repair capability is associated with developing lung cancer, especially in nonsmokers. XPC participates in the initial recognition of DNA damage during the DNA nucleotide excision repair process. We hypothesize that inactivation of XPC by promoter hypermethylation may play an important role in the reduction of DNA repair capability to cause p53 mutation during lung carcinogenesis. In this report we demonstrate that hypermethylation of 17 CpG islands between À175 and À1 of the XPC promoter correlates very well with XPC expression levels in eight lung cancer cell lines. When cells with hypermethylated XPC promoters were treated with the demethylating agent 5-aza-2 0 -deoxycytidine, XPC expression was de-repressed. Interestingly, XPC hypermethylation was found in 4 of 5 (80%) lung cancer cell lines harbored p53 mutation, but not observed in two lung cancer cells which had a wild-type p53 gene. Among the analysis of the hypermethylation status of 158 lung tumors, XPC hypermethylation is more common in nonsmokers (39 of 94, 41%) than in smokers (14 of 64, 22%; P ¼ 0.010). Additionally, XPC hypermethylation is more often with G-T or G-C mutations in the p53 gene. To verify whether XPC inactivation is involved in the occurrence of p53 mutation, XPC gene of A549 cells was knockdown by a small interference RNA and then XPC-inactivated cells were treated with benzo[a]pynrene for different passages. Surprisingly, G-T mutation in p53 gene at codon 215 was indeed detected in XPCinactivated A549 cells of passages 15 and confirmed by loss of transcription activity of mdm2. These results show that hypermethylation of the XPC promoter may play a crucial role in XPC inactivation, which may partly contribute to the occurrence of p53 mutations during lung tumorigenesis, especially nonsmokers.