In the current study, we found: (1) both TrkB and BDNF were up-regulated in CDDP resistant HNSCC cell lines (2) a molecular phenotype consistent with apoptotic resistance was associated with acquired CDDP resistance expression (3) exogenous BDNF can induce a CDDP-resistance in CDDP-sensitive cells (4) modulation of TrkB expression resulted in XiAP, Bim, and MDR1 dysregulation, which contributed to CDDP resistance (5) a phenotype that was driven in part by dysfunction Akt signaling mediates CDDP resistance in HNSCCs. The gene discussed is BDNF; the disease is head and neck squamous cell carcinoma.