Single-nucleotide polymorphisms (SNPs) of TERT-rs2736098 (C > T) and CLPTM1L-rs401681(C > T) at the 5p15.33 locus are significantly associated with cancer risk as reported in genome-wide association studies (GWAS), but there are no reported studies for squamous cell carcinoma of the head and neck (SCCHN). In a case-control study of 1079 SCCHN cases and 1115 cancer-free controls of non-Hispanic whites who were frequency matched by age and sex, we genotyped for these two SNPs and assessed their associations with SCCHN risk. Compared with the CC genotypes of each polymorphism, the associations of a slightly reduced risk of SCCHN with the variant genotypes of CT + TT of both polymorphisms were approaching statistical significance [Odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.76-1.08 for TERT-rs2736098 and OR = 0.86, 95% CI = 0.71-1.04 for CLPTM1L-rs401681, respectively]. When the two SNPs were combined, the variant genotypes of the two SNPs were significantly associated a moderately reduced risk of SCCHN (OR = 0.82, 95% CI = 0.67-0.99), and the number of variant genotypes was associated with a significantly reduced risk in a dose-response manner (P = 0.028). Furthermore, the reduced risk was more pronounced in ever smokers, ever drinkers and patients with oropharyngeal cancer. Our results suggested that these two SNPs at the 5p15.33 locus may be associated with a reduced risk of SCCHN, particularly for their combined effect. Although we added additional evidence for the association of the two SNPs with cancer risk as reported in GWAS, additional studies are needed to replicate our findings.