Squamous cell carcinoma of the head and neck (SCCHN) is a relatively rare cancer with a poor prognosis. In the present study, we investigated susceptibility biomarkers for SCCHN in 155 Koreans (73 SCCHN cases and 82 controls). Expression of the xeroderma pigmentosum group C (XPC) DNA-repair gene was measured by TaqMan fluorogenic real-time RT-PCR using RNA isolated from peripheral blood samples. In addition, the XPC-PAT genotype [an intronic and biallelic poly(AT) insertion/deletion polymorphism] was determined by PCR of peripheral blood DNA. Among known environmental and physical risk factors, age, gender, tobacco smoking, and alcohol consumption were associated with the SCCHN risk (P < 0.01). Lower XPC expression levels were found for the SCCHN cases, particularly in the larynx, than for the controls (P < 0.05); the geometric means (standard deviations) of XPC expression normalized by 18S rRNA in the cases and controls were 5.89 (8.13) and 15.14 (9.77), respectively. However, the distributions of the XPC-PAT genotypes were similar in the cases and controls. In addition, there were no associations between the expression of XPC and the PAT genetic polymorphism. XPC expression was not affected by age, gender, tobacco smoking, or alcohol consumption. After adjusting for SCCHN-associated lifestyle factors, the effective strength of XPC expression on SCCHN risk was weaker (0.05 < P < 0.1) than those of tobacco smoking and age (P < 0.05). There was a positive association between XPC mRNA expression in blood and SCCHN tissues (n = 9; P < 0.01); therefore, peripheral blood appears to be a reasonable surrogate tissue for XPC expression in tumor tissue. In conclusion, the XPC-PAT polymorphism had no effect on XPC expression or SCCHN risk. However, XPC expression may influence SCCHN risk.