Background The prognosis of patients with non-small cell lung cancer (NSCLC) who develop leptomeningeal metastasis (LM) is poor. Objective To assess the clinical efficacy of osimertinib, a third-generation tyrosine-kinase inhibitor (TKI), in patients with epidermal growth-factor receptor ( EGFR )-mutated NSCLCs and LM. Patients and Methods Retrospective study of NSCLC patients with osimertinib-treated EGFR -mutated NSCLC and LM. Results Twenty patients (mean age, 61.2 years; 70% women) with adenocarcinoma NSCLC were included in the study. EGFR mutations were reported in exons 18 ( n  = 2), 19 ( n  = 7), and 21 ( n  = 11). Before starting osimertinib, patients had received a mean of 2.3 treatment lines. When LM was diagnosed, all patients had clinical symptoms. Sixteen (80%) patients had a performance status ≥2. At osimertinib initiation, 13 (65%) patients harbored the EGFR -T790M–resistance mutation. Osimertinib was started at 80 ( n  = 17), 160 ( n  = 2), or 40 mg/day ( n  = 1). All 13 (100%) patients with the T790M mutation and 4 (57%) of those without it obtained clinical responses. Among the 11 radiologically assessable patients, 9 (82%) responded, with 5 responses reported within 15 days after treatment initiation. Median overall survival and progression-free survival were 18.0 and 17.2 months, respectively, from the start of osimertinib. Conclusions In this non-selected population, osimertinib had remarkable efficacy in NSCLC patients with LM irrespective of the presence of the EGFR -T790M–resistance mutation. Osimertinib efficacy was rapid in several patients, even some with poor performance status.