Human papillomavirus (HPV) type 16 infection is an etiologic factor in a subset of head and neck squamous cell carcinomas (HNSCC). It is unknown if host genetic susceptibility modifies the HPV16-HNSCC association. DNA samples collected as part of a Boston area case-control study of HNSCC were genotyped for single-nucleotide polymorphisms (SNPs) from the National Cancer Institute's SNP500Cancer database. Analysis of demographic, phenotypic and genotypic data for 319 HNSCC cases and 495 frequency-matched controls was performed using unconditional logistic regression. All reported P-values are two sided. We identified a polymorphism in the sodium-dependent vitamin C transporter SLC23A2 that modifies the risk of HNSCC associated with HPV16 infection. Among those with a wild-type allele at SLC23A 2, the risk of HNSCC associated with HPV16-positive serology was 5.0 (95% confidence interval (CI) = 3.2-7.8). However, among those with a homozygous variant genotype, the risk of HNSCC associated with HPV16 was attenuated [odds ratio (OR) = 2.8; 95% CI = 1.2-6.2]. Further, when we tested whether genotype modified the interaction between citrus exposure, HPV16, and HNSCC, we found a dramatically increased risk of HNSCC for those with a wild-type SLC23A2 allele, HPV16-positive serology and high citrus intake (OR = 7.4; 95% CI = 3.6-15.1). These results suggest that SLC23A2 genetic variation alters HPV16-associated HNSCC while also highlighting the important role of citrus exposure in this disease.