Background Leptomeningeal metastasis (LM) is a detrimental complication of advanced non-small-cell lung cancer (NSCLC), and the optimal therapeutic approach for LM patients is in shortage. This retrospective study aimed to investigate the clinical features and prognostic factors of NSCLC patients with LM. Methods We retrospectively reviewed the medical records of NSCLC patients with LM at the Shandong Cancer Hospital and Institute between July 2014 and March 2018. Identified cases had pathology-proven NSCLC with either positive cerebrospinal fluid cytology or leptomeningeal enhancement by MRI. Results One hundred and thirty-six NSCLC patients (58 men, 78 women) with LM were enrolled in the retrospective study; median age was 55 years (range, 29-89 years). Fifty-one patients harbored EGFR mutations, ALK rearrangement was detected in 6 patients. Treatment for LM consisted of EGFR-TKIs alone in 11 patients, whole brain radiotherapy (WBRT) alone in 19 patients, Chemotherapy (ChT) alone in 12 patients, EGFR-TKIs plus WBRT in 30 patients, WBRT plus ChT in 25 patients, and EGFR-TKIs plus ChT in 24 patients. The median progression-free survival was 3.9 months (95% confidence interval [CI]: 3.178-4.622), and the median overall survival (OSLM) was 9.8 months (95% CI:7.5-12.1). Thirty patients who received WBRT plus EGFR-TKIs achieved longer survival than those who only received WBRT (median 13.6 vs 8.8 months; P = 0.027), but did not add any survival benefit than those only received EGFR-TKIs (median 13.6 vs 13.9 months; P = 0.352). A multivariate analysis indicated that KPS >= 80 (hazard ratio [HR] = 0.592, 95% CI:0.369-0.95; P = 0.03) and EGFR-TKIs (HR = 0.507, 95% CI:0.283-0.908; P = 0.022) after LM diagnosis were independent favourable predictors of survival, whereas smoking (HR = 1.181, 95% CI:1.009-3.246; P = 0.047) was an independent predictor of poor survival. Conclusions Our results suggest that patients with good performance statuses, non-smoking patients, and the administration of EGFR-TKIs might improve clinical outcomes in NSCLC patients with LM.