DNMT3B -283T/C (rs6087990) SNP was associated with a higher risk of head and neck squamous cell carcinoma (HNSCC) on comparison with the C group in the codominant model for both T/C and C/C genotypes (OR = 2.58; 95% CI = 1.59–4.18; p < 0.001 and OR = 1.86; 1.08–3.22; p < 0.001, respectively) and dominant (OR = 2.32; 1.46–3.69; p < 0.001) and overdominant models (OR = 1.81; 95% CI = 1.26–2.59; p = 0.001). This evidence concerns the gene DNMT3B and head and neck squamous cell carcinoma.