OBJECTIVES: Uniportal subxiphoid video-assisted thoracoscopic (SVATS) surgery for major lung resections is a new approach, but clinical evidence is lacking. The aim of this study was to examine our experience with the use of the uniportal subxiphoid approach in video-assisted thoracoscopic (VATS) major lung resections and lymph node dissections. METHODS: From October 2014 to August 2015, 153 patients with early-stage non-small-cell lung carcinoma (NSCLC) and benign disease underwent uniportal subxiphoid VATS major lung resections. Patients were placed in a lateral position with 60-70° inclination, and a 4- to 5-cm midline median or transverse incision was made below the sternocostal triangle. A 10-mm 30° video camera and VATS instruments were used through the same single incision. Perioperative variables and outcomes were collected prospectively and analysed retrospectively. RESULTS: Of the 153 patients who underwent surgery with the uniportal subxiphoid VATS approach, 105 had lobectomies and 48 had segmental resections; 135 cases of lung cancer and 18 cases of benign pulmonary disease were noted. Right upper lobectomy was the most common procedure (51%), and left upper lobectomy was the most time-consuming procedure (190 ± 21 min). The mean operating time was 166.9 ± 12.6 min; the average volume of blood loss was 127.5 ± 27.6 ml. In patients with lung cancer, the mean total number of lymph node stations explored was 3.4 ± 0.8. The duration of chest drain use was 2.6 ± 0.2 days. The length of hospital stay was 4.3 ± 0.4 days. Perioperative arrhythmia was the most common complication (13% of cases). Prolonged air leak was the cause of prolonged hospital stay. Five cases were converted to conventional VATS due to technical difficulties, and eight cases were converted to thoracotomy due to major bleeding. Postoperative 30-day mortality was zero and there were no re-admissions. All cases had a R0 complete cancer resection on histology. CONCLUSIONS: Uniportal subxiphoid VATS lobectomy/segmentectomy is a feasible and safe procedure for early-stage lung cancer and benign disease.