Uniportal video-assisted thoracoscopic surgery (U-VATS) has recently become an alternative approach for many minimally invasive thoracic procedures, but although its surgical effectiveness has been proven, still its feasibility and safety are debated and unclear. the objective of this study was to compare the safety and perioperative outcomes of U-VATS versus multiportal VATS (M-VATS). This was a comparative follow-up randomised controlled clinical trial, carried out on 36 randomly selected eligible patients, and fulfilling the inclusion and exclusion criteria for VATS, they were assigned randomly into two groups: Study Group I including 18 patients undergoing U-VATS with conventional treatment using standard chest tube drainage and Control Group II including 18 patients undergoing M-VATS) with the same conventional treatment using standard chest tube drainage and served as a comparable control group. Patients in the U-VATS Group 1 had faster operation time, and with reduced blood loss, pleural drainage and post-operative hospitalisation, they also experienced lower average post-operative pain score on comparison with those in M-VATS Group II (P < 0.001), respectively. For either group, there were no hospital deaths or infections. There was no noticeable difference between the two groups in terms of the number of resected lymph nodes or the rates of intraoperative or post-operative complications (P > 0.05). U-VATS is feasible and safe in eligible selected patients with favourable short-term perioperative outcomes (operative time, duration of pleural drainage, post-operative pain, early ambulation, duration of hospital stay as well as the risk of perioperative complications), and it can be considered the preferred approach in minimally invasive thoracic procedures that open up for the possibility of fast-track thoracic surgeries.