Background: A Phase I trial has been completed to examine the safety and feasibility of combining bevacizumab (bev) with radiation and cisplatin in patients with locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). We assessed the capacity of bev monotherapy to induce tumor response as measured by functional imaging and biomarker evaluation. We report preliminary clinical outcome as well as correlative imaging and biomarker results. Methods: All patients underwent experimental imaging [FLT-PET (proliferation), CuATSM-PET (hypoxia), DCE-CT scans (flow/perfusion)] and biomarker evaluation prior to bev monotherapy. At three weeks, repeat tumor biopsy and imaging/serum studies were performed. Comprehensive H&N chemoradiation (CRT) was then delivered to 70 Gy in 33 fractions with concurrent weekly cisplatin at 30 mg/m2 and Q3 week bev (wks 1, 4, 7) with dose escalation from 5 to 10 to 15 mg/kg. Results: Between 2007-2010, ten LA-HNSCC pts were enrolled. All had stage IV HNSCC and remain alive (9 NED) with a mean survival of 22.4 months. There have been two recurrences at 15 and 16 months respectively. Nine patients experienced grade 3 toxicity (dysphagia-9, mucositis-7, tumor pain-3, weight loss-4, nausea/vomiting-2), with two cases of grade 4 lymphopenia. No significant bleeding was observed. Tumor proliferation (FLT) following bev monotherapy and at mid-course showed significant reduction (p<0.05). Tumor hypoxia (Cu-ATSM) showed minimal change following bev alone, but showed reduction during CRT. AQUA histology confirmed reduction in VEGFR2 expression from tumor biopsies following bev therapy. Conclusions: The incorporation of bev with comprehensive CRT for LA-HNSCC appears safe and feasible. Several patients manifested tumor regression following administration of bev alone. Three patients experienced pronounced tumor pain early in the treatment course. Experimental imaging and biomarker evaluation demonstrated clear changes following bev alone and during CRT. These findings may afford opportunities to forecast clinical outcome for individual patients and thereby tailor therapy approaches in future clinical trials.