Objective To determine the effect of epidural block on the incidence of postoperative complications in the patients undergoing video-assisted thoracoscopic surgery for non-small cell lung cancer (NSCLC). Methods A total of 396 NSCLC patients undergoing radical thoracoscopic surgery in our hospital from January 2014 to November 2015 were subjected in this study. They were randomly given general anesthesia and postoperative intravenous analgesia (GA group, n=198) and combined epidural-general anesthesia and postoperative epidural analgesia (EGA group, n=198). Except epidural block, the 2 groups received general anesthesia with same drugs intraoperatively and intravenous or epidural patient-controlled analgesia postoperatively for 3 d. The severities of pain at rest and with cough were assessed during the first 3 postoperative days with numeric rating scale (NRS). The patients were followed up from the 4th day postoperatively until hospital discharge for postoperative complications, hospital length of stay and in-hospital mortality. The primary end point was the incidence of postoperative complications during hospitalization. Results All 396 patients were included in the intention-to-treat analysis. The NRS pain scores both at rest and with cough were significantly lower in the EGA group than the GA group during the first 3 postoperative days (all P<0.0001). Compared with the GA group, the EGA group had significant lower incidences of atelectasis [1.0%(2/198) vs 4.5%(9/198), P=0.032], atrial fibrillation [2.0%(4/198) vs 5.1%(14/198), P=0.016], and overall cardiovascular complications [2.5%(5/198) vs 8.1%(16/198), P=0.014]. But there was no significant difference in the overall incidence of complications after surgery [15.2%(30/198) vs 12.6%(25/198), P=0.468]. The incidence of hypotension requiring intervention was obviously higher (P=0.021), whereas that of hypertension requiring intervention was lower (P<0.0001) in the EGA group than in the GA group during the perioperative period. Conclusion For the patients undergoing video-assisted thoracoscopic surgery for lung cancer, epidural block provides better analgesia and reduced the incidences of atelectasis and atrial fibrillation after surgery. However, it increases the occurrence of perioperative hypotension.