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Objectives: Preoperative selection bias led to the inability to generalize the proposed benefit of subxiphoid uniportal video-assisted thoracoscopic surgery (SVATS) as having less postoperative pain than uniportal intercostal VATS. So, we conducted this prospective, single-blinded, randomized controlled trial to investigate the hypothesis that SVATS may have less early postoperative pain than UVATS in patients who undergo major lung resection for early-stage lung cancer., Methodsa Total of: 262 patients were randomly allocated between 2 groups (each with 131 patients), the first being the UVATS group and the second being the SVATS group. The values indicated on the numerical rating scale (NRS) of pain were collected at 24 h and 48 h during rest and during coughing. In addition, different perioperative variables were analysed and compared between the 2 groups., Results: Multiple linear regression analysis showed that the type of surgical approach was a significant predictor of the postoperative NRS values. The postoperative NRS pain values were significantly lower in the SVATS group after 24 h during rest and coughing and after 48 h during coughing. Postoperatively, patients in the SVATS group got out of bed significantly earlier [16.37 (2.54) vs 18.05 (3.29) h, p < 0.001]. The SVATS group showed a significantly higher rate of intraoperative arrhythmia [20 (15.3%) vs 3 (2.3%) patients, p = 0.03]., Conclusions: SVATS major pulmonary resection in early-stage lung cancer is associated with less early postoperative pain than the UVATS approach. Operating on patients with cardiac problems using the SVATS approach is still a limiting factor for randomization due to the potential compression on the heart with resulting arrhythmia., Clinical Trial Registration: The trial was registered under clinical trials.gov Identifier: NCT03331588. https://clinicaltrials.gov/ct2/show/NCT03331588., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)