The aim of our study was to evaluate the treatment of post-radiotherapy recurrent mediastinal nodal metastasis. Post-radiotherapy esophageal cancer patients with mediastinal lymph node recurrence were enrolled in this study. Patients were randomized into the radiation (±chemotherapy) or the chemoablation group. Patients randomized to the chemoradiotherapy group received additional radiotherapy, second-line chemotherapy, or both. Patients randomized to the chemoablation group received CT-guided percutaneous chemical ablation. Clinical remission was assessed at 1 month by contrast CT. Reirradiation dose ranged from 2,200 to 3,600 cGy depending on dose-limiting constraints in consideration of prior radiotherapy dose. The RECIST criteria were used in the evaluation of response to therapy. The median length of follow-up is 6 months. Thirty-one patients were enrolled in the study. In the chemoradiation group, all patients underwent CT imaging at 1-month follow-up. Among these patients, seven had progressive disease, five had stable disease (SD), and four had partial response (PR). The 6-month survival rate was 12.5%. In the chemoablation group at 1-month follow-up, 12 patients had SD and three patients had PR, and the 6-month survival rate was 46.6%. Our results suggest that chemoablation therapy as salvage treatment after post-radiotherapy relapse is efficacious and safe.