For the first time, our data show preliminary indication that inherited alterations of DNA MMR pathway, related to MSH3 rs26279, EXO1 rs1047840 and EXO1 rs9350 SNPs, modify toxicity and response to chemoradiation in HNSCC, and may contribute to future personalized treatment of patients. This evidence concerns the gene MSH3 and head and neck squamous cell carcinoma.