Background: Vorinostat (Zolinza) is a potent HDAC inhibitor that sensitizes head and neck squamous cell carcinoma (HNSCC) to cytotoxic therapy while sparing normal epithelium The primary objective of this study was to determine the maximally tolerated dose (MTD) of Vorinostat in combination with concurrent chemoradiation therapy. Secondary and tertiary endpoints included therapeutic response and delineation of acute and late toxicities. Methods: Twenty seven of 29 consented patients with Stage III/IV unresectable HNSCC completed the protocol. Patients received Vorinostat in combination with standard cisplatin/carboplatin chemotherapy (every 21 days) and intensity modulated radiation therapy (IMRT, 70Gy). Doses of Vorinostat were escalated in sequential cohorts of three patients. Toxicities were determined using standard NCI-CTCAEv4.03. Dose limiting toxicities (DLT) were defined as any adverse event of Grade 3 or higher. Results: Of the 27 patients on this study, 17/27 were p16/HPV+. The MTD of Vorinostat was 200mg delivered on M,W,F in combination with concurrent chemoradiation therapy. Twenty five of 27 patients (92.59%) had a complete response (CR) to therapy and 24/27 (88.89%) are alive and disease-free at a mean follow-up of 32.1 months (range 2-66 months). Two patients (7.41%) had residual disease at the completion of therapy and died of disease. One patient had a CR but developed lung metastases at 12 months. He is currently alive with disease at 38 months. The regimen was well tolerated and resulted in no treatment breaks during radiotherapy. Patients experienced a mean weight loss of 11.69% (range 0.79-20.61%) along with low rates of radiation related dermatitis (22/27 Grade 1) and oral mucositis (0/27 Grade 4, 15/27 Grade 3, 6/27 Grade 2, 6/27 Grade 1). No patient developed osteoradionecrosis, 4/27 developed pharyngeal stenosis and 1/27 developed Grade 3 xerostomia. Conclusions: Vorinostat in combination with concurrent chemoradiation therapy is a safe and highly effective treatment regimen. There was a high rate of complete response to therapy with toxicity rates comparable, if not more favorable, to existing treatment standards. Clinical trial information: NCT01064921