The aim of the present study was to investigate the effectiveness of 125I particle implantation during R2resection for non-small cell lung cancer (NSCLC). Data from 23 patients with NSCLC and macroscopic residual diseasefollowing surgery (R2 resection) between March 2010 and May 2014 were retrospectively analyzed. Among these patients, 12 patients [4 with T-residual disease (incomplete resection of primary tumor but complete dissection of regional lymph node), 8 with N-residual disease (complete resection of primary tumor but incomplete resection of metastatic regional lymph node)] underwent 125I particle implantation during the operation, while the other 11 (4 with T-residual disease and 7 with N-residual disease) received postoperative conventional radiotherapy. The local control rate, overall survival, and distant metastasis were evaluated. Additionally, the efficacy and safety of brachytherapy using 125I particle implantation during surgery for locally advanced NSCLC were investigated. The 23 patients were followed up for 3–40 months. For the 125I group, the 2-year local control rate was 100%, and the median survival time was 24 months. The 1–2-year survival rates were 83.3 and 58.33%, respectively. For the postoperative radiotherapy group, the median survival time was 12 months, andthe 1- and 2-year survival rates were 54.5 and 27.7%, respectively. No statistically significant difference in 2-year survival rates was detected between the two treatment groups, but the particle implantation group exhibited a higher survival rate trend. For patients with T-residual disease, the survival rate was higher for the 125I seed implantation group compared with the postoperative radiotherapy group. However, there was no significant difference in the rates of metastasis between the two groups for patients with N-residual disease. Therefore, intraoperative implantation of 125I particles during R2 resection of NSCLC may be a safer and more reliable method to reduce the local recurrence rate compared with conventional radiotherapy. Although not statistically significant, the overall survival rate of patients in the 125I seed implantation group was higher compared with the postoperative radiotherapy group.