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. The gene discussed is TP53; the disease is head and neck squamous cell carcinoma.