Objective: The aim of this study is to determine the efficacy of indocyanine green (ICG) conjugated to antiepidermal growth factor receptor antibody (cetuximab) to image head and neck cancer. Study Design: Mice (n = 3) were injected with unconjugated ICG and imaged at 100-second intervals for a total of 1000 seconds to assess imaging characteristics. Mice (n = 10) xenografted with SCC-1 cells were then systemically injected with cetuximab conjugated to indocyanine green and imaged over a 72-hour period. To assess the sensitivity and specificity, xenografted tumors underwent subtotal resections and then were assessed for residual disease by fluorescence stereomicroscopy and confirmed by histology. Results: Tumors demonstrated excellent fluorescence 24 hours after injection of cetuximab-ICG. There was a direct relationship between fluorescence and the given dose of cetuximab-ICG. Following subtotal resection, we found fluorescence correlated with a sensitivity of 78.4% and specificity of 96%. Conclusions: This study provides evidence that supports further preclinical investigation of cetuximab in the evaluation of surgical margins, but linkage to ICG lacks the sensitivity for use in a clinical setting. © 2007 American Academy of Otolaryngology-Head and Neck Surgery Foundation.