Abstract Despite advances in operative technology, intraoperative methods for primary tumor and lymph node detection have not changed in the past 30 years. To this end, we propose to use a fluorescent and nuclear labeled anti-EGFR antibody (panitumumab) for targeted dual modality imaging (TDMI) of the primary tumor and lymph nodes in head and neck squamous cell carcinoma (HNSCC) In this application, we propose to use labeled panitumumab since it has been successful in several early-stage studies, we introduce two novel concepts for intraoperative detection of very small (1 mm3) tumor deposits. First, we combine the high-resolution/depth-limited imaging properties of optical imaging agents with the low-resolution/not depth-limited properties of nuclear agents. Second, we show that these two agents can be systemically administered for the detection of tumor-positive lymph nodes. We provide extensive clinical data in HNSCC to demonstrate that tumor fragments less than 1 mm3 in size can be detected using anti-EGFR antibody (panitumumab) as the targeting molecular to fulfill the needs of PAR-20-295 entitled, ‘Optical fluorescent methods and technologies for sensitive cancer detection in vivo’. While use of anti-EGFR antibodies for imaging alone is not innovative, innovation should be considered in the context of PAR- 20-295 which requires applications use “…probes with previously demonstrated capabilities for the detection of small tumors”. To this end, we introduce dual modality imaging and leveraging this for molecular imaging lymph nodes. This study is designed to meet FDA guidelines for a surgical imaging trials. Patients eligible for head and neck cancer resection will receive a systemic administration of an anti- EGFR antibody (panitumumab) labeled with either IRDye800 (pan800) or 111Indium (111In-pan) for fluorescent and nuclear signal, respectively. After systemic administration of both agents, a SPECT/CT will be performed to identify the location of tumor-positive margins and tumor-positive lymph nodes. The patient will then undergo resection of the primary tumor and neck dissection using fluorescent and gamma probe guidance (while maintaining the standard of care). We hypothesize that introduction of targeted dual modality imaging (TDMI) will improve intraoperative decision making.