Background Recurrent head and neck squamous cell carcinoma (rHNSCC) represents a significant global health burden with an unmet medical need. In this study we determined the safety and efficacy of RM‐1929 photoimmunotherapy in patients with heavily pretreated rHNSCC. Methods RM‐1929 (anti‐EGFR–IR700 dye conjugate) was infused, followed by tumor illumination. We evaluated safety, tumor response, and pharmacokinetics. Results Nine patients were enrolled in Part 1 (dose‐finding) and 30 patients in Part 2 (safety and efficacy). No dose‐limiting toxicities were experienced in Part 1; 640 mg/m2 with fixed light dose (50 J/cm2 or 100 J/cm) was recommended for Part 2. Adverse events (AEs) in Part 2 were mostly mild to moderate but 19 (63.3%) patients had AE ≥Grade 3, including 3 (10.0%) with serious AEs leading to death (not treatment related). Efficacy in Part 2: unconfirmed objective response rate (ORR) 43.3% (95% CI 25.46%–62.57%); confirmed ORR 26.7% (95% CI 12.28%–45.89%); median overall survival 9.30 months (95% CI 5.16–16.92 months). Conclusions Treatment was well tolerated. Responses and survival following RM‐1929 photoimmunotherapy in heavily pretreated patients with rHNSCC were clinically meaningful and warrant further investigation. Clinical Trial Information NCT02422979.