BACKGROUND: Conventional video-assisted thoracoscopic surgery (VATS) lobectomy for locally advanced non-small cell lung cancer (NSCLC) is a feasible and safe surgery in high-volume centers with significant VATS experience. Uniportal VATS lobectomy has been recently been reported to be a promising, less invasive approach. The purpose of this study is to explore the safety and feasibility of uniportal video-assisted thoracoscopic surgery (U-VATS) for the treatment of patients with locally advanced NSCLC. METHODS: From January 2013 to September 2015, a total of 132 patients with locally advanced NSCLC underwent U-VATS or open thoracotomy major pulmonary resections and standard mediastinal lymph node dissection. Patients were divided into two groups: (I) locally advanced NSCLC underwent U-VATS (U-VATS); (II) locally advanced NSCLC underwent open thoracotomy (open). A descriptive and retrospective study was performed, including the operative time, operative blood loss, postoperative chest tube duration, postoperative hospital stay, lymph node dissection, postoperative complications and postoperative recovery. RESULTS: A total of 132 patients with locally advanced NSCLC were included in this study: 64 (U-VATS) . 68 (open) patients. The patient demographic data was similar in both groups. Median operative time (157.0 . 160.6) and median number of lymph nodes (35.5 . 32.5) were similar in both groups. Chest tube duration and hospital of stay were statistically shorter in U-VATS group while rate of complications were higher in open thoracotomy group. One patient died on the 55 postoperative day because of tumor metastasis and bronchopleural fistula. A higher percentage of patients who underwent UVATS resections were able to receive adjuvant therapy timely compared to the open group. CONCLUSIONS: Uniportal VATS major pulmonary resections and mediastinal lymph node dissection is a safe and feasible procedure for the treatment of locally advanced NSCLC. Particularly it is suitable for the frail patients with locally advanced NSCLC who require comprehensive treatment.