In summary, our data showed that GSTT1 and ERCC1 c.354C>T SNVs, independently and in combination with other SNVs (TP53 c.215G>C, GSTP1 c.313A>G, MLH1 c.93G>A, and MSH3 c.3133A>G), act as independent factors for CDDP‐induced nephrotoxicity in HNSCC patients treated with CDDP chemoradiation through their impact on detoxification capacity, DNA repair, and apoptosis efficiency. This evidence concerns the gene MLH1 and head and neck squamous cell carcinoma.