Background: Leptomeningeal metastasis (LM) is one of the most severe complications of non-small cell lung cancer (NSCLC) and always accompanied with poor prognosis. Furmonertinib is a pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with high brain penetration and wide therapeutic window. This study aimed to evaluate the efficacy and safety of high-dose furmonertinib in patients with EGFR-mutated NSCLC and LM in the real world. Methods: Eligible patients were aged at least 18 years old and had histological or cytological confirmed advanced NSCLC harboring an EGFR mutation. Patients were diagnosed as probable or confirmed LM according to the EANO-ESMO criteria. Patients were treated with furmonertinib 240mg once daily. The primary endpoint was overall survival (OS), time to treatment discontinuation (TTD) and clinical response rate were secondary endpoints. Clinical response rate assessed with improvement of neurologic symptoms or signs and changes in the performance status. Additional efficacy evaluations included changes in brain magnetic resonance imaging (MRI) according to the RANO-LM radiologic criteria. Results: Between May 1, 2021, and December 28, 2023, 48 patients were enrolled at Henan Cancer Hospital. All of the enrolled patients had poor performance status, 13 (27.1%) patients had an ECOG score of 2, 35 (72.9%) patients had an ECOG score of 3. And 35 (72.9%) patients had received other 3rd generation EGFR-TKIs. The median follow-up time was 15 months. 31 OS events occurred at the data cut-off. The primary endpoint of median OS was 8.433 months (95%CI, 5.481 to 11.386 months). The secondary endpoint of median TTD was 8.267 months (95%CI, 5.395 to 11.138 months). The clinical response rate was 75%. The LM objective response rate (ORR) and disease control rate (DCR) assessed by investigator according to RANO-LM radiologic criteria were 47.4% and 92.1%, respectively. The adverse event profiles were consistent with previous reports of furmonertinib. 22 (45.8%) patients had adverse events (AEs) possibly related to furmonertinib. 3 (6.3%) patients had grade 3 elevated aminotransaminase or nausea or leucopenia, respectively, leading to dose reduction to 160mg daily. Conclusions: In the real world, high-dose furmonertinib demonstrated significant clinical efficacy and tolerable safety in patients of EGFR-mutated NSCLC with LM, even in patients who had been treated with other 3rd generation EGFR-TKIs previously. Clinical trial information: ChiCTR2300072092.