Background: Leptomeningeal disease (LMD) is characterized by tumor metastasis to the membranes and cerebrospinal fluid (CSF) surrounding the brain and spinal cord. This devastating complication confers a poor overall survival (OS) measured in weeks for untreated patients. Melanoma has one of the highest rates of dissemination to the leptomeninges. The advances in targeted and immune therapies have revolutionized OS for patients with melanoma systemic metastases and there is a growing number of individual case reports showing clinical responses to these agents in patients with melanoma-LMD (M-LMD) . However, few studies have examined the association between these and other therapies with the OS of a large cohort of melanoma-LMD (M-LMD) patients. Methods: M-LMD patients treated at Moffitt Cancer Center between 2011 and 2020 were retrospectively identified. M-LMD diagnosis was confirmed radiographically via magnetic resonance imaging (MRI) and/or positive CSF cytology indicating the presence of malignant cells. Demographic data and pre/post LMD diagnosis treatment data were collected and analyzed using the Kaplan-Meier method to determine factors that improve OS. Results: 86 M-LMD patients were identified. 50 were male and 36 were female, but patient gender did not have an impact on OS. 53 patients were diagnosed via MRI only and 33 patients had positive CSF cytology confirming M-LMD diagnosis. 34 patients did not receive any treatment post-LMD diagnosis and had a median OS of 3.72 weeks, while 52 patients receiving treatment (i.e. systemic, intrathecal [IT], and/or whole brain radiation therapy [WBRT]) had a median OS of 10.80 weeks (p < 0.0001). More specifically, 30 patients receiving targeted BRAF/MEKi treatment had an 18.8 week median OS compared to 6.68 weeks for the 56 patients who did not receive such treatments (p = 0.0015). Furthermore, 44 patients received immune therapy and had a median OS of 12.00 weeks compared to 5.88 weeks for those who did not (p = 0.002). The 16 Patients that received IT chemotherapy had a prolonged median OS when compared to the 70 patients who did not (9.72 weeks vs 4.72 weeks, p = 0.009). Furthermore, WBRT also improved median OS in the 22 patients that received the therapy (15.72 weeks vs 7.88 weeks, p = 0.0007). The 36 patients that received BRAF/MEKi treatment prior to their LMD diagnosis had a slightly shorter OS (7.00 weeks) compared to the 46 patients that did not receive such treatment beforehand (10.80 weeks, p = 0.005). Conclusions: The current data supports the use of systemic, IT, and radiation therapies to prolong OS for M-LMD patients; however, the OS for these patients remains grim despite advances in such therapies. Further research is necessary to understand the pathophysiology of LMD, and new clinical trials are urgently needed to identify novel therapies that improve M-LMD prognosis.