The primary objective was to determine the sensitivity and specificity of epithelial cell adhesion molecule (EpCAM) immunoflow cytometry circulating tumor cells (CTC) analysis in CSF in patients with suspected leptomeningeal metastases (LM). The secondary objective was to explore the distribution of driver mutations in the primary tumor, plasma, cell free CSF (cfCSF), and isolated CTC from CSF in non-small cell lung cancer (NSCLC). We tested the performance of the CTC assay vs CSF cytology in a prospective study in 81 patients with a clinical suspicion of LM but a nonconfirmatory MRI. In an NSCLC subcohort, we analyzed circulating tumor (ct)DNA of the selected driver mutations by digital droplet PCR (ddPCR). The sensitivity of the CTC assay was 94% (95% confidence interval CI 80-99) and the specificity was 100% (95% CI 91-100) at the optimal cutoff of 0.9 CTC/mL. The sensitivity of cytology was 76% (95% CI 58-89). Twelve of the 23 patients with NSCLC had mutated epidermal growth factor receptor ( ). All 5 tested patients with LM demonstrated the primary driver mutation in cfCSF. The driver mutation could also be detected in CTC isolated from CSF. CTC in CSF are detected with a high sensitivity for the diagnosis of LM. ddPCR can determine mutations in both cfCSF and isolated CTC from CSF of patients with -mutated NSCLC and LM. This study provides Class III evidence that EpCAM-based immunoflow cytometry analysis of CSF accurately identifies patients with LM.