Background: Patients with recurrent HNSCC (rHNSCC) have limited therapeutic options and poor prognosis. We report promising results of a Phase 2a trial of photoimmunotherapy (PIT) for the treatment of rHNSCC using a novel targeted light activated drug RM-1929; a conjugate of the EGFR-directed monoclonal antibody cetuximab with the phthalocyanine dye, IRDye 700DX. Methods: A multi-institutional, open label Phase 2a study of rHNSCC patients who could not be satisfactorily treated with surgery, radiation, or platinum chemotherapy was conducted to evaluate the safety and efficacy of RM-1929. For each treatment, non-thermal red light was applied to the tumors 24 hours after intravenous infusion of RM1929. Light was applied by surface illumination for superficial disease or interstitial illumination via intratumoral placement of fiber optic diffusers for deep tumors. Therapeutic response was calculated using CT RECIST 1.1 determined by an independent blinded radiologist. Results: Thirty rHNSCC patients were enrolled in this Phase 2a trial. Safety data are currently evaluable from 30 subjects, outcome data from 28 subjects. There were no dose-limiting toxicities or skin photosensitivity reactions observed. SAEs reported to be possibly related to study treatment, included treatment site pain, tumor hemorrhage, and swelling. Objective response rate was 28% (8/28), complete response was 14% (4/28). Median progression free survival for 28 evaluable patients was 173 days (5.7 months). Median overall survival for the entire 30 patient cohort was 278 days (9.1 months). Conclusions: Photoimmunotherapy with RM1929 in patients with rHNSCC is safe and well tolerated. CT RECIST 1.1 PFS, ORR and CR response rates are improved over those of standard therapies in this heavily pre-treated population. Future clinical trials are planned to evaluate the therapeutic potential of RM1929 alone or in combination with other treatment modalities. Clinical trial information: NCT02422979