INTRODUCTION AND OBJECTIVES: Leptomeningeal disease (LMD) involves disseminating cancer cells to the leptomeninges and cerebrospinal fluid. The impact of intracranial parenchymal brain metastases and extracranial disease burden at LMD diagnosis remains unclear. This study evaluates these factors alongside local and systemic therapies before and after LMD diagnosis. METHODS: A retrospective analysis was conducted on 188 patients diagnosed with LMD between 2011 and 2024. Data on demographics, imaging findings, and treatments were collected. Kaplan-Meier estimates were used for survival analysis, and independent prognostic factors were identified using a backward-stepwise Cox regression model. RESULTS: Primary cancers included breast cancer (34.0%), non-small cell lung cancer (22.3%), and melanoma (14.4%). LMD was diagnosed via MRI in 56.4% of cases, cerebrospinal fluid (CSF) cytology in 2.7%, and both in 41.0%. Median overall survival was 2.8 months [95% CI: 2.4 - 3.7]. Independent prognostic factors for improved survival included male sex (HR: 0.61 [95% CI: 0.40 - 0.93], p = 0.020), absence of hydrocephalus at LMD diagnosis (HR: 0.42 [95% CI: 0.22 - 0.79], p = 0.007), and targeted therapy post-diagnosis (HR: 0.33 [95% CI: 0.20 - 0.55], p <
0.001). Two or more lines of systemic therapy before LMD diagnosis increased mortality risk (HR: 1.73 [95% CI: 1.16 - 2.59], p = 0.007). Lack of CNS parenchymal disease at LMD diagnosis also increased risk (HR: 0.51 [95% CI: 0.30 - 0.89], p = 0.017). Pre-diagnosis radiation therapy showed no survival benefit, while post-diagnosis radiation improved outcomes (HR: 0.47 [95% CI: 0.32 - 0.70], p <
0.001). CONCLUSION: Absence of hydrocephalus and use of targeted therapy post-diagnosis are favorable prognostic factors, while extensive prior systemic therapy and CNS parenchymal disease worsen outcomes. Tailored therapies addressing intracranial disease are crucial for improving survival in LMD patients.