BACKGROUND: Recently, the incidence of multiple pulmonary nodules (MPNs) is gradually rising. Therefore, this study aims to evaluate the safety and efficacy of computed tomography (CT)-guided radiofrequency ablation (RFA) combined with video-assisted thoracoscopic surgery (VATS) for patients with MPNs. MATERIAL AND METHODS: The clinicopathological data and perioperative results of the patients with MPNs who underwent RFA combined with VATS at our center from October 2022 to September 2024 were reviewed. The primary endpoints were the safety and feasibility of this combined technique. RESULTS: A total of 105 patients were enrolled in this study, including 30 males and 75 females with a mean age of 55.1 years. In total, 293 lesions were treated, 113 of which were ablated and 180 were surgically resected. The mean nodule size was 6.58 mm for ablated nodules and 10.3 mm for resected nodules. Of the 113 nodules treated using RFA, 112 were ground-glass nodules. The median ablation time and power of RFA were 5 min and 60 W, respectively. Of the 180 surgically resected nodules, 169 had ground-glass opacity. Total postoperative complication morbidity was 9.5% (10/105), with major complications (Clavien-Dindo classification ≥ 3) in 1.0% (1/105). No perioperative deaths occurred, and the median hospital stay was 5 days (range, 5-7 days). Notably, no recurrence has been observed in any patients during the short-term follow-up period. CONCLUSIONS: Our study demonstrated that CT-guided RFA combined with VATS is a safe and feasible therapeutic technique for the patients with MPNs. Given the increasing incidence of MPNs, this combination strategy holds significant potential for clinical application.