Objective: The aim of this study was to identify the clinical features and prognostic factors of leptomeningeal metastasis (LM) in non-small cell lung cancer (NSCLC) patients undergoing treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Methods: Twenty-five cases of NSCLC with LM, treated in our hospital during January 1, 2003 to October 31, 2013, were enrolled in this study. Medical records were reviewed for clinical features and treatments, and the survival and prognostic factors were analyzed. Results: NSCLC-LM were more common in female patients (64.0%), and most were adenocarcinomas (72.0%). Twenty (80.0%) patients underwent anti-cancer treatment, among them 17 patients underwent EGFR-TKIs treatment.The median overall survival (mOS) after the diagnosis of LM was 4.9 months for the whole group (25 cases). Patients receiving EGFR-TKIs treatment had a longer median survival than patients not receiving EGFR-TKIs (5.3 months vs. 1.2 months, P=0.022). Eleven patients who developed LM before the targeted therapy had a prolonged median survival of 8.1 months after EGFR-TKIs treatment. The univariate analysis showed that female gender and EGFR-TKIs treatment were favorable prognostic factors influencing the survival (P<0.05), while age, LM at the time of initial diagnosis, LM developed during the EGFR-TKIs treatment, whole-brain radiotherapy (WBRT), intrathecal chemotherapy, or systemic cytotoxic chemotherapy were not associated with mOS (P>0.05 for all). The multivariate analysis showed that female gender (P=0.012) and EGFR-TKIs treatment (P=0.008) were significant predictors of a good prognosis. Conclusions: EGFR-TKIs treatment may confer benefit for NSCLC-LM patients. Female patients and EGFR-TKIs treatment are favorable prognostic factors for survival.