BACKGROUND: While there have been prior reports on pulmonary nodule (PN) localization through computed tomography (CT)-guided soft hook-wire (SHW) placement, there remains a dearth of studies specifically focused on the CT-guided SHW localization of multiple PNs. This study was thus designed to specifically evaluate the efficacy and safety of this localization strategy in patients with multiple PNs. METHODS: In total, 43 consecutive patients with multiple PNs underwent CT-guided SHW localization followed by video-assisted thoracoscopic surgery (VATS) to resent these PNs in our hospital between January 2022 and December 2022. A control group consisting of 140 individuals who underwent the CT-guided SHW localization of a single PN during the same interval was also selected. Both groups were analyzed retrospectively for safety and efficacy outcomes. RESULTS: The final study population included 43 patients (94 PNs) in the multiple PN group, and 140 patients (140 PNs) in the single PN group, with all patients having undergone CT-guided SHW localization of these PNs. A one-stage procedure was employed for the localization of multiple PNs. The respective rates of technical success for SHW localization in the multiple and single PN groups were 98.9% and 100% (P = 0.402). The duration of localization in the multiple PN group was significantly longer than that in the single PN group (P = 0.001). The respective pneumothorax rates in the multiple and single PN groups were 32.5% (14/43) and 15.7% (22/140) (P = 0.015), while the corresponding lung hemorrhage incidence rates were 48.8% (21/43) and 36.4% (51/140) (P = 0.145). All PNs successfully underwent limited VATS resection, with a one-stage VATS procedure having been used for the resection of multiple PNs in a given patient. CONCLUSIONS: CT-guided SHW localization is a safe and effective means of localizing multiple PNs in a single patient. This simultaneous localization of multiple PNs can provide effective guidance for the subsequent one-stage limited VATS resection of these nodules.