Objective To evaluate the efficacy and safety of intraoperative pleural irrigation with nocardia rubra cell-wall skeleton (N-CWS) for reducing pleural effusion drainage after radical surgery for lung cancer. Methods A retrospective analysis was conducted on the clinical data of lung cancer patients who underwent lobectomy and mediastinal lymph node dissection at the First Affiliated Hospital of Xiamen University between December 2024 and May 2025. Patients were divided into a control group and an irrigation group based on the intraoperative use of N-CWS. Patients in the irrigation group received pleural irrigation with 800 μg of N-CWS diluted in 10 mL of normal saline. The following outcomes were compared between the two groups: pleural effusion drainage volume at 0-24 h, 24-48 h, and 48-72 h postoperatively; degree of air leak; chest tube duration; postoperative length of stay; and the incidence of adverse events (fever, chest pain, and vomiting). Results A total of 245 patients were included (97 males, 148 females) with a mean age of (61.28±6.26) years, with 205 in the control group and 40 in the irrigation group. Compared to the control group, the irrigation group showed significantly lower pleural effusion drainage volumes at 0-24 h, 24-48 h, and 48-72 h, as well as shorter chest tube duration and postoperative length of stay (all P<0.05). There was no significant difference in the degree of postoperative air leak (P=0.801). No significant differences were observed between the two groups regarding the highest body temperature within 72 h post-surgery (P=0.130), fever grade (P=0.450), severity of chest pain (P=0.138), or the incidence of nausea and vomiting (P=0.376). ConclusionIntraoperative pleural irrigation with N-CWS in patients undergoing lobectomy and mediastinal lymph node dissection for lung cancer can significantly reduce postoperative pleural effusion drainage volume, shorten chest tube duration, and decrease the length of hospital stay. The procedure is safe and feasible.