We found that carriers of the AKT1 rs1130233 TT genotype, dominance model (CT+TT vs. CC), recessive model (TT vs. CT+CC), and the AKT1 rs2494732 CC genotype had a reduced risk of HNSCC (P<0.05), whereas those with the PIGR rs291097 GA genotype, dominance model (GA+ AA vs. GG), and PIGR rs291102 dominance model (GA+ AA vs. GG) showed increased risk of HNSCC (P<0.05). Here, PIGR is linked to head and neck squamous cell carcinoma.