Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). In this non-therapeutic study, we enrolled 12 patients with MBC and known or suspected LMD who were undergoing a lumbar puncture as part of clinical care and collected extra cerebrospinal fluid (CSF) and a paired blood sample from each patient at a single time point. Of the 12 patients, 7 patients are confirmed to have LMD based on positive cytology and/or convincing MRI imaging (LMD^pos), and 5 patients are deemed not to have LMD based on similar criteria (LMD^neg). Using high-dimensional, multiplexed flow cytometry, we profile and compare the CSF and peripheral blood mononuclear cell (PBMCs) immune populations between patients with LMD and those without. Patients with LMD observe a lower overall frequency of CD45⁺ cells (29.51% vs. 51.12%, p < 0.05), lower frequencies of CD8⁺ T cells (12.03% vs. 30.40%, p < 0.01), and higher frequency of T_regs than patients without LMD. Interestingly, the frequency of partially exhausted CD8⁺ T cells (CD38^hiTIM3^lo) is ~6.5-fold higher among patients with LMD vs. those without (2.99% vs. 0.44%, p < 0.05). Taken together, these data suggest that patients with LMD may have lower overall immune infiltrates than patients without LMD, suggesting a more permissive CSF immune microenvironment but a higher frequency of partially exhausted CD8⁺ T cells, which may offer an important therapeutic target.