Inherited polymorphisms of DNA repair genes may contribute to variations in DNA repair capacity and genetic susceptibility to cancer. In a hospital-based case-control study of 287 non-Hispanic white patients with newly diagnosed SCCHN and 311 control subjects matched on age, sex, ethnicity, and smoking status, we investigated the role of a newly identified variant allele of XPC, XPC-PAT1. We found that the frequency of the XPC-PAT1 allele was higher in the cases (0.409) than in the controls (0.333; P 5 0.007). Fifty cases (17.4%) and 37 controls (11.9%) were XPC-PAT1/1, and 135 (47.0%) cases and 133 controls (42.8%) were XPC-PAT1/2. XPC-PAT1/2 and XPC-PAT1/1 subjects were at significantly increased risk for SCCHN [adjusted odds ratios 5 1.44 and 1.85, respectively (95% confidence intervals, 1.01-2.05 and 1.12-3.05, respectively; trend test, P 5 0.007)]. We did not find ethnic difference in the frequency of XPC-PAT1 allele among four groups aged between 19 and 75 years: non-Hispanic whites, 294; African-Americans, 178; Hispanic-Americans, 103; and native Chinese, 119 (0.333, 0.281, 0.296, and 0.353, XPC-PAT1 allele may contribute to the risk of developing SCCHN.