Background: Retinoic acid is important for cell growth, differentiation, and apoptosis, which when dysregulated may predispose the development of cancer. Retinoic acid metabolism can be influenced by ethanol, cigarette smoking, and areca nut, the three major risk factors of head and neck cancer (HNC). A previous genome-wide association study reported an association between serum retinol level and two single nucleotide polymorphisms (SNPs) in two retinol transporter genes (TTR rs1667255 and RBP4 rs10882272) (1). The current study assesses the association between these two SNPs and HNC risk. Methods: 133 incident cases of HNC and 128 sex- and age- matched controls were recruited from the department of otolaryngology and department of stomatology. Data on the use of alcohol, cigarette, and areca nut were ascertained through in-person interview. Genotyping of TTR rs1667255 and RBP4 rs10882272 was performed using the Taqman-based real-time PCR method. Unconditional logistic regression was performed to estimate HNC risk associated with the two SNPs. Results: No association between HNC risk and TTR rs1667255 or RBP4 rs10882272 was observed. However, the two SNPs appeared to modify the relationship between alcohol consumption and HNC risk. There was an increased risk of HNC associated with daily alcohol drinking only among subjects with the “high serum retinol genotypes” (CC for TTR rs1667255: odds ratio (OR) = 4.6, 95 confidence interval (CI): 1.3-16.3; TT for RBP4 rs10882272: OR = 2.3, 95% CI: 1.2-4.4). While daily alcohol drinking was not associated with an increased risk of HNC among subjects with the “low serum retinol genotypes” (AA or AC for TTR rs1667255: OR = 1.4, 95% CI: 0.7-2.9; TC or CC for RBP4: OR = 0.7, 95% CI: 0.1-3.6). Conclusion: The association between alcohol consumption and HNC risk is modified by the polymorphisms of retinol transporter genes. Reference: 1. Mondul AM, Yu K, Wheeler W, et al. Genome-wide association study of circulating retinol levels.