BACKGROUND: To evaluate the efficacy and safety of diffusing alpha-emitter radiation therapy (DaRT) for recurrent head and neck cancer (rHNC) after radiotherapy. METHODS: This study was a multicenter prospective clinical trial. Eligibility criteria included all patients with biopsy-proven rHNC and history of radiotherapy. The efficacy of DaRT was evaluated in terms of tumor shrinkage after 10 weeks of DaRT seed implantation. To assess safety of DaRT, radioactivity levels in blood and urine were measured, and incidence and grade of adverse events (AEs) were evaluated. RESULTS: Between 2019 and 2021, DaRT was performed in 11 patients and completed in 10 patients with 11 tumors. The tumor sites included the tongue (n = 3), buccal mucosa (2), lips (2), floor of the mouth (1), soft palate (1), nose (1), and subcutaneous layer (1). Nine tumors were confirmed to be squamous cell carcinoma, and the remaining two tumors were basal cell carcinoma and neuroblastoma. Complete response (CR) and partial response (PR) were observed in three and six patients, respectively. The response rate was 81.8%. The maximum average radioactivity levels in blood and urine were 42.5 Bq/cm CONCLUSION: The initial response of rHNC after radiotherapy to DaRT was favorable, and the incidence and grade of AEs were acceptable, as compared to existing therapies.