OBJECTIVES: The objective of this study was to evaluate the efficacy and safety of CT-guided radioactive I-125 seed implantation as a salvage treatment for locally recurrent head and neck soft tissue sarcoma (HNSTS) after surgery and external beam radiotherapy. METHODS AND MATERIALS: From December 2006 to February 2018, 25 patients with locally recurrent HNSTS after surgery and external beam radiotherapy were enrolled. All the patients successfully underwent CT-guided I-125 seed implantation. The primary end points included the objective response rate (ORR) and local progression-free survival (LPFS). The secondary end points were survival (OS) and safety profiles. RESULTS: After I-125 seed implantation, the ORR was 76.0%. The 1-, 3-, and 5-year LPFS rates were 65.6%, 34.4%, and 22.9%, respectively, with the median LPFS of 16.0 months. The 1-, 3-, and 5-year OS rates were 70.8%, 46.6%, and 34.0%, respectively, with the median OS of 28.0 months. Furthermore, univariate analyses showed that the recurrent T stage and histological grade were prognostic factors of LPFS, whereas only the histological grade was a predictor of OS. The major adverse events were skin/mucosal toxicities, which were generally of lower grade (<= Grade 2) and were well tolerated. CONCLUSIONS: Radioactive I-125 seed implantation could be an effective and safe alternative treatment for locally recurrent HNSTS after failure of surgery and radiotherapy. Recurrent T stage and histological grade were the main factors influencing the efficacy. (C) 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.