Objective To compare the feasibility and safety of video-assisted thoracoscopic surgery (VATS) under non-intubated, intravenous anesthesia with spontaneous ventilation. Methods A total of 80 patients undergoing VATS (48 wedge resections, 8 sympathectomies, 24 pleural biopsies) between January 2015 and June 2017 were included. Those patients were randomized into two groups. The 40 patients were enrolled as a treatment group (19 males and 21 females at age of 23.3±10.2 years) and received surgery under non-intubated intravenous anesthesia with spontaneous ventilation. And the other 40 patients were enrolled as a control group (21 males and 19 females at age of 22.2±9.9 years) and received surgery under routine intravenous anesthesia with intubated ventilation. Results Comparing with the control group, the patients of the treatment group had lower white blood cell count (5.8×109±2.4×109 vs. 7.3×109±3.6×109, P<0.001), lower gastrointestinal adverse reaction rate (7.5%vs. 27.5%, P=0.002), lower sore throat rate (5.0% vs. 30.0%, P<0.001), lower cough grade (0.9±0.3vs 2.1±0.5, P<0.050), shorter drainage time (1.8±1.6 dvs. 3.7±1.8 d, P<0.050) and shorter hospital stay (2.3±1.8 dvs. 5.8±2.3 d, P<0.050). Conclusion Video-assisted thoracoscopic surgery under non-intubated, intravenous anesthesia with spontaneous ventilation is safe and feasible, which also has certain advantages in reducing the postoperative complications and promoting patients' quick recovery from surgery.