Genetic alterations in NSD1 hold potential as novel prognostic biomarkers in HPV(-) head and neck cancers. NSD1 mutations in HPV(+) cancers may also play a prognostic role, although this effect must be examined in a larger cohort. NSD1 downregulation results in improved sensitivity to cisplatin and carboplatin, but not to other DNA-damaging agents, in epithelial cells. Increased sensitivity to platinum-based chemotherapy agents associated with NSD1 depletion may contribute to improved survival in HPV(-) HNSCCs. Further studies are needed to determine mechanisms through which NSD1 protects HPV(-) HNSCC cells from platinum-based therapy, as well as confirmation of NSD1 effect in HPV(+) HNSCC.