Abstract: Objective To investigate the efficacy of osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), in the treatment of EGFR mutation-positive (EGFR m+) non-small cell lung cancer (NSCLC) complicated with malignant pleural effusion (MPE). Methods Retrospective analysis was conducted on 262 patients with advanced EGFR m+ NSCLC who received first-line osimertinib treatment at the Affiliated Hospital of Xuzhou Medical University from 2021 to 2025. Among them, 158 patients had MPE (observation group) and 104 patients did not have MPE (control group). According to MPE treatment methods, the observation group was further divided into three subgroups: closed chest drainage (group A), cisplatin pleural perfusion (group B), and cisplatin combined with recombinant human vascular endothelial growth inhibitor pleural perfusion (group C). Patient characteristics, efficacy, survival, and adverse reactions were analyzed. Results The observation group showed significantly higher serum levels of CEA and CA125 than the control group (P<0.05). The objective response rate (ORR) and disease control rate (DCR) were lower in the observation group than in the control group (P<0.05). The median progression-free survival (mPFS) and overall survival (mOS) were shorter in the observation group compared to the control group (P<0.05). Group C had superior mPFS and mOS compared to groups A and B (P<0.05), with good safety. Conclusions MPE is a poor prognostic factor for osimertinib treatment in EGFR m+ NSCLC. Osimertinib, in combination with cisplatin and recombinant human vascular endothelial growth inhibitor pleural perfusion, can improve survival outcomes in patients while maintaining good safety