Abstract: Objective To evaluate the clinical value of nebulized indocyanine green (ICG) combined with near-infrared fluorescence imaging for intraoperative detection of air leaks during pulmonary resection. Methods This was a two-center randomized controlled trial enrolling patients undergoing thoracoscopic pulmonary resection. After enrollment, patients were randomly divided into an experimental group and a control group. The experimental group received nebulized ICG and fluorescence imaging in addition to the conventional water immersion test, while the control group underwent the water immersion test alone. Intraoperative air leak detection and postoperative air leak incidence were compared between the two groups. Multivariable logistic regression analysis was performed to assess the association between ICG nebulization intervention and postoperative air leaks after adjusting for confounding factors including age, sex, smoking history, history of respiratory disease, surgical procedure, and study center. Results A total of 181 patients were enrolled (90 in the experimental group, 91 in the control group). The experimental group showed significantly higher intraoperative air leak detection rate (37.8% vs.19.8%, P=0.003) and median number of detected air leaks0 (0, 1) vs.0 (0, 0), P=0.004 compared with the control group. The proportion of patients developing postoperative air leaks was significantly lower in the experimental group than in the control group (25.6% vs.50.5%, P<0.001), and the median chest tube duration was significantly shorter3 (2, 4) vs.4 (3, 5) days, P=0.008. Multivariable logistic regression analysis showed that ICG nebulization intervention was an independent protective factor against postoperative air leaks (OR=0.34, 95% CI:0.17-0.68, P=0.002). The mean time for ICG nebulization was 37 seconds, and no ICG-related adverse events occurred in any patient during the intraoperative period or within one month postoperatively. Conclusions Nebulized ICG combined with near-infrared fluorescence imaging significantly improves intraoperative detection of air leaks, reduces the incidence of postoperative air leaks, and shortens chest tube duration. This technique is convenient, safe, and holds important clinical value for application.