A recent genome-wide association study (GWAS) reported significant associations of several novel genetic variants with risk of upper aerodigestive tract (UADT) cancers including head and neck cancer (HNC) in Europeans. However, these findings have not been confirmed in other populations including Chinese. According to the findings from the GWAS and other publications, we genotyped six genetic variants (rs1494961, rs1229984, rs1789924, rs971074, rs4767364, and rs671) in a case–control study with 397 HNC cases and 900 controls in China, by using the TaqMan allelic discrimination assay. We found that rs1229984 at 4q23 significantly increased the risk of HNC [dominant model: adjusted odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.05–1.71; additive model: adjusted OR = 1.24, 95% CI = 1.04–1.50], while rs671 at 12q24 significantly decreased the risk of HNC (recessive model: adjusted OR = 0.46, 95% CI = 0.25–0.85). Furthermore, when these two loci were evaluated together by the number (0–4) of putative risk alleles (rs1229984 G and rs671 G), a significant locus–dosage effect was found between the groups and risk of HNC (Ptrend = 0.016). Compared with the “0–1” group, groups with “2” risk alleles and “3–4” risk alleles significantly increased the risk of HNC with adjusted ORs of 1.17 (95% CI = 0.84–1.64) and 1.51 (95% CI = 1.06–2.15), respectively. However, no significant association was detected between other four variants (rs1494961, rs1789924, rs971074, and rs4767364) and HNC risk. These findings suggest that rs1229984 at 4q23 and rs671 at 12q24 may serve as candidate markers for susceptibility to HNC in Chinese population. © 2012 Wiley Periodicals, Inc.