Optical fluorescent technology has the potential to deliver real time imaging of cancer into the operating room and the clinic. To determine the efficacy of fluorescently labeled anti-vascular endothelial growth factor (VEGF) antibody to be used as a cancer specific optical contrast agent to guide surgical resections, we evaluated the sensitivity and specificity of this agent to detect microscopic residual disease in a preclinical model of head and neck squamous cell carcinoma (HNSCC). Using a flank murine model, mice were xenografted with SCC-1 tumor cells and injected with anti-VEGF antibody (bevacizumab) conjugated to an optically active fluorophore (Cy5.5). Tumors underwent sub-total resections and were assessed for the presence of residual disease by fluorescent stereomicroscopy. Expected positive and negative biopsies were taken according to the presence or absence of fluorescence, respectively. Histology was used to confirm the presence or absence of disease. Biopsies taken from areas of fluorescence within the wound bed (n=18) were found to be histologically malignant in all but one biopsy. Samples taken from a non-fluorescing tumor bed (n=15) were found to be histologically benign in 11 of 15. These findings correlated with a sensitivity and specificity of 80.9% and 91.7%, respectively. This data supports previous data presented by this group and supports further investigation of fluorescently labeled anti-tumor antibodies to detect disease in the surgical setting.