Purpose: The study evaluated the feasibility, clinical effectiveness, and quality of life of computed tomography (CT)-guided I-125 brachytherapy for locally recurrent nasopharyngeal carcinoma (NPC). Methods: We recruited 81 patients diagnosed with locally recurrent NPC after previous radiotherapy with or without chemotherapy. Thirty-nine patients received I-125 brachytherapy (group A) and 42 received re-irradiation (IMRT, group B). The evaluated outcomes were local control, complications, and quality of life. Cox proportional hazards regression analysis was used to compare local tumor progression-free survival (LTPFS) and overall survival (OS) in the two treatment groups. Results: The median follow-up was 30 months (range, 5-68 months), median LTPFS was 21 in group A and 17 months in group B. The 1-, 2-, and 3-year OS in group A were 84.6%, 51.3%, 30.7%, and 85.7%, 50.0%, and 32.6% in group B. In group A, 10/39 patients (25.6%) experienced at least one >= grade III complication; no grade V complications occurred. In group B, 28/42 (66.7%) experienced at least one >= grade III complication and 6/42 (14.3%) died of severe grade V complications. No significant between-group difference existed in the Quality of Life score on the EORTC QLQ-H&N35 questionnaire before treatment. In group A, quality of life was significantly improved after treatment; but did not improve, or even deteriorated in group B. Conclusions: I-125 brachytherapy was a feasible, safe, and effective treatment for locally recurrent NPC. I-125 brachytherapy significantly reduced complications caused by re-irradiation and improved patients' quality of life.