Laryngeal cancer treatment is confined to surgery, radiation therapy and chemotherapy. However, laryngeal cancer often develops resistance to conventional therapy and still lacks strong molecular prognostic biomarker for treatment stratification. Therefore, researchers evaluated genetic alterations (including somatic mutation and copy number alteration), epigenetics and gene expression data of 256 SCCHN (squamous cell carcinoma of head and neck) patients to further identify the high-risk patient group who may benefit from aggressive treatment. The results showed that the methyltransferase NSD1 and NSD2 genetic alterations are associated with better prognosis in the 63 laryngeal cancer study cohort. Surprisingly, these findings are different from other non-laryngeal form of head and neck cancer, indicating no correlation between NSD mutations and prognosis. In conclusion, though larger studies is still necessary to further confirm the functional roles of NSD mutations, this study indicated the prognostic value of NSD mutations in laryngeal cancer and may become the therapeutic target for drug development in the future.