Targeting tumor vasculature is an emerging strategy in cancer treatment. Promising results have been shown in preclinical studies when vascular disrupting agents (VDAs) are used in combination with other anticancer therapies. Because radiation therapy with concurrent cisplatin or cetuximab has become standard treatment for patients with locally advanced head and neck squamous cell carcinoma (HNSCC), we investigated whether the VDA ombrabulin (AVE8062) could improve the antitumor activity of radiation plus cisplatin and radiation plus cetuximab combinations. HNSCC HEP2 or FaDu tumor bearing mice were treated with ombrabulin, cisplatin, cetuximab, local radiation therapy or combinations of these treatments. Ombrabulin attenuated tumor growth of HEP2 and FaDu xenografts compared to control tumors. A more pronounced tumor growth delay and tumor regression were induced when ombrabulin was added to local irradiation, cisplatin or cetuximab in FaDu tumors compared to single agent treatments. Finally, triple agent therapies combining ombrabulin, irradiation, and either cisplatin or cetuximab were more effective than double combination treatment regimens and increased tumor growth delay in both HEP2 and FaDu tumor models. Of note, complete tumor regression was achieved in FaDu tumor model for the triple combination including platinum. Immunohistochemistry on FaDu tumors demonstrated a specificity of ombrabulin towards intratumoral vessels, in contrast to peritumoral vasculature. Our results provide a rationale for the use of ombrabulin in combination with two standard treatment regimens that are concurrent cisplatin-based chemoradiation and cetuximab plus ionizing radiation therapies, for the treatment of HNSCC.