Background To determine the safety, preliminary efficacy, pharmacokinetics, and immunogenicity of a single cycle of RM-1929 photoimmunotherapy, an anti-EGFR antibody cetuximab conjugated with a light-activatable dye (IRDye ® 700DX), in Japanese patients with recurrent head and neck squamous cell carcinoma (rHNSCC). Methods Patients received a single fixed dose (640 mg/m 2 ) of RM-1929 and a fixed light treatment dose (50 J/cm 2 for superficial illumination; 100 J/cm fiber diffuser length for interstitial illumination). Safety, tumor response (modified RECIST v1.1 by central radiology review), pharmacokinetics, and immunogenicity were evaluated. Results Three Japanese patients were enrolled who had failed ≥ 3 prior lines of therapy including radiation, chemotherapy, cetuximab, and immunotherapy. Target lesions were: submental lesion; right superficial cervical node lesion and oropharynx lesion; and external auditory canal lesion. All patients experienced ≥ 1 treatment-emergent adverse event (TEAE), but none were considered dose-limiting. TEAEs were mild to moderate in severity except for one grade 3 application-site pain, which was transient, resolved without sequelae within 24 h, and did not affect study treatment administration. Thirteen of 17 TEAEs reported were possibly or probably related to study treatment. Three patient reports of application-site pain and localized edema were deemed probably related to study treatment. Objective response was observed in two patients (both partial responses). The third patient had disease progression. RM-1929 concentrations and pharmacokinetic parameters were similar in all patients. No patients tested positive for anti-drug antibodies. Conclusions RM-1929 photoimmunotherapy showed a manageable safety profile in rHNSCC. Tumor response in these heavily pre-treated patients was clinically meaningful and warrants further investigation. Clinical trial registration The trial was registered with the Japanese registry of clinical trials as jRCT2031200133.