Background: Genetic polymorphisms in the 3' untranslated regions (3' UTRs) targeted by miRNAs alter the strength of miRNA binding in a manner that affects the behaviour of individual miRNAs. An insertion (Ins)/deletion (Del) polymorphism (rs3783553) in the 3' UTR of IL-1 alpha may disrupt a binding site for miRNA-122. IL-1 alpha plays an important role in inflammation, immunity and defense against infection. Thus, we hypothesised that the rs3783553 polymorphism affects individual susceptibility to human papillomavirus (HPV)-associated oral squamous cell carcinoma (OSCC). Methods: We genotyped the rs3783553 polymorphism; and determined HPV16 L1 serology, tumour HPV16 DNA and serum IL-1 alpha expression. Univariate/multivariable logistic regression models were used to calculate associations. Results: We found that HPV16 L1 seropositivity alone was associated with an increased risk of OSCC (Odds ratio (OR), 3.1; 95% confidence interval (CI), 2.1-4.6), and the risk of HPV16-associated OSCC was modified by the rs3783553 polymorphism. Patients with both HPV16 L1 seropositivity and Del/Del genotype for the rs3783553 had the highest risk of OSCC when using patients with HPV16 L1 seronegativity and Ins/Del + Ins/Ins genotypes as a comparison group. Notably, that effect modification was particularly pronounced in several subgroups (e.g. SCCOP, never-smokers and never-drinkers). The patients with Del/Del genotype were approximately 3.0 times more likely to have HPV16-positive squamous cell carcinoma of the oropharynx (SCCOP) tumours compared to those patients with Ins/Del + Ins/Ins genotypes. Additionally, functional relevance of this variant was characterised to explore the genotype-phenotype correlation. Conclusion: These results suggest that IL-1 alpha 3' UTR rs3783553 polymorphism may be functional and influence susceptibility to HPV16-associated OSCC, particularly for SCCOP. Validation of our findings is warranted. (C) 2015 Elsevier Ltd. All rights reserved.