Background: Patients (pts) with metastatic breast cancer (MBC) and leptomeningeal disease (LMD) have a poor prognosis with limited therapeutic options. It is critical to better understand the risk factors and natural history of this condition, including pts in a modern cohort. Methods: In this single center retrospective cohort study, we identified pts with radiographic and/or cytologic evidence of LMD who received care at the University of California San Francisco (UCSF) from 2000-2023. To identify pts, we used the UCSF Pathology Database, the UCSF Radiation Oncology Database, and EMERSE, a searchable copy of the medical record. We conducted chart review to identify demographic and clinical characteristics, treatment history, and overall survival (OS). Results: 106 pts with MBC and radiographic and/or cytologic evidence of LMD were identified. All but one pt was female (n=105; 99.1%); most pts were non-Hispanic (n=93, 87.7%) and white (n=74, 69.8%). Median age at the time of MBC diagnosis was 51.9 years; 25 pts (20%) had de novo metastatic disease. Most pts had invasive ductal carcinoma (n=71, 66.9%), with invasive lobular carcinoma making up 21.7% (n=23) of cases. Pts presented with the following BC subtypes: Hormone receptor (HR) positive, HER2 negative (n=50, 47.1%), HR+/HER2+ (n=19, 17.9%), HR-/HER2+ (n=9, 8.5%), and triple negative (TNBC; n=23, 21.7%). Most pts had brain metastasis (n=78, 73.6%) in addition to LMD. Median time from diagnosis of MBC to LMD was 17.6 months (0-101.2 months). Pts received a median of 3.0 lines of therapy prior to the diagnosis of LMD (range 0-11.0) and 1.0 lines after the diagnosis of LMD (range 0-4.0). Many pts received intrathecal (IT) therapy (n=42, 39.6%) and/or whole brain radiation therapy or spinal radiation (n=49, 46.2%). Median OS from the diagnosis of LMD to death was 3.3 months. There was no significant difference in median OS by subtype: HR+/HER2- 3.5 months, HER2+ 4.7 months, and TNBC 2.2 months (p=0.45). There was no significant difference in median OS by histology: ductal (3.3 months) vs. lobular (4.7 months) (p=0.56). Pts who received IT therapy survived longer than those not treated with IT therapy (4.7 vs. 2.5 months, p=0.01). There was no significant difference in median OS among pts diagnosed with LMD between 2000-2015 (2.9 months) vs. 2016-2023 (3.6 months) (p=0.74). Conclusions: This study represents one of the largest reported case series of pts with MBC and LMD, including a more modern cohort. There appeared to be an over-representation of pts with lobular cancer and those with de novo metastatic disease. Most pts had brain metastases in addition to LMD. Survival was short in all pts, particularly those who did not receive IT therapy. There was no significant difference in median OS in pts diagnosed with LMD from 2000-2015 vs. 2016-2023; this remains an area of unmet clinical need.