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Simple Summary: Almost a third of breast cancer patients may develop cancer that spreads to the brain or the tissue around it, with a higher risk for those with HER2-positive cancers. For these patients, using cerebrospinal fluid (CSF) as a liquid biopsy is a promising way to track the disease, guide treatment, and predict outcomes. This study looked at CSF samples from three patients with brain metastases (seen on scans but not confirmed by lab tests) and compared them to blood samples. Cancer cells were found in the CSF, but not in the blood, and were further studied to reveal a group of cancer cells that looked different from one another. Overall, the results suggest that CSF could be a useful tool for diagnosing and tracking cancer in these patients. Background/Objectives: Up to 30% of patients with breast cancers will develop brain or leptomeningeal metastases, and this risk is especially high with HER2-positive cancers. For patients with central nervous system metastases, cerebrospinal fluid (CSF) liquid biopsies are a promising opportunity to monitor disease, inform treatment, and predict prognosis. This pilot study investigated CSF liquid biopsy analytes from three patients diagnosed with central nervous system metastases based on imaging but not confirmed via clinical cytology. Methods: The detection of cellular analytes with the non-enrichment high-definition single-cell assay (HDSCA3.0) workflow was compared between the CSF and matched peripheral blood (PB) samples. Results: Circulating tumor cells (CTCs) were detected in the CSF but not the PB and were subsequently molecularly characterized using single-cell genomics and targeted multiplexed proteomics to reveal a clonal population of phenotypically heterogeneous cells. There was a lack of concordance in the copy number alteration profiles between CTCs and cell-free DNA (cfDNA) in the CSF. Extracellular vesicle surface marker analysis in CSF revealed a prominent signal among tetraspanins (CD9/CD63/CD81), with CD81 exhibiting the highest signal across all patients. Conclusions: The data presented suggest that CSF could be a useful tool for diagnosing and assessing disease severity. [ABSTRACT FROM AUTHOR]