Purpose: To compare the efficacy and safety of computed tomography (CT)-guided 125 I seed implantation with second-line chemotherapy in treatment of oligorecurrence non-small cell lung cancer after failure of first-line chemotherapy.Methods: Data of oligorecurrence non-small cell lung cancer patients after failure of first-line chemotherapy at two institutions were retrospectively reviewed from January 2013 to July 2018. A total of 53 patients who received the treatment of 125 I seed implantation or second-line chemotherapy were eligible for this study. In group A, 25 patients, 84 lesions, received CT-guided permanent 125 I seed implantation, whereas in group B, 28 patients, 96 lesions, received second-line chemotherapy. The outcomes were measured in terms of disease control rate, overall survival, quality of life, and complications.Results: The median follow-up period was 13 months (range, 5-42 months). Disease control rate in group A was higher than that in group B (70.8 vs. 42.3%, P = 0.042) at 6 months after treatment. The median overall survival was 12.8 months (95% confidence interval, 10.5-15.1 months) in group A and 15.2 months (95% confidence interval, 12.2-18.2 months) in group B, with no significant difference (P = 0.847). Since the fourth month, the number of patients in group A with a non-decreasing Karnofsky Performance Scale score was more than that in group B (P < 0.05). The incidence of grade 3 or higher complications especially hematologic toxicity in group A was significantly lower than that in group B (P < 0.05).Conclusion: Radioactive 125 I seed implantation is safe and feasible in selected non-small cell lung cancer patients with oligorecurrence after failure of first-line chemotherapy and seems to provide a better long-term quality of life in these patients compared with second-line chemotherapy.