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The differentiation of benign versus malignant hematologic processes on cerebrospinal fluid (CSF) is difficult given the significant morphologic overlap and frequently scant specimen. Our study compared the diagnostic power of cytomorphologic analyses and FC analyses in the context of CSF hematologic malignancies. We identified 32 cases of CSF submitted for cytopathologic analysis with corresponding FC data, histologic, or clinical follow-up. The slides were blinded and the study participants (one hematopathologist, two cytopathologists, and one cytotechnologist) reviewed the key slides of each case without additional information. These diagnoses were compared with the original diagnoses made in the context of clinical information and ancillary studies. The spectrum of disease ranged from acute myeloid leukemia, mantle cell lymphoma, chronic lymphocytic lymphoma, Burkitt lymphoma, large cell lymphoma, T cell lymphoma, and non-Hodgkin lymphoma. Parallel diagnoses were made in 62.5% of the cases. Interestingly, the correct diagnoses were rendered in 73% of benign cases, compared with 52% of malignant cases. Of the malignant cases, there was a higher proportion of correct diagnosis based on morphology in the acute malignancies (67%) versus the chronic malignancies (47%). The sensitivity, specificity, positive predictive value, and negative predictive value were 73, 52, 60, and 66% respectively. Features most useful for diagnosis of malignancy included cellular monotony and nuclear contour irregularity. The diagnosis of malignancy based on morphology alone is difficult in CSF. Ancillary studies such as FC analyses greatly enhance the ability to accurately distinguish between benign and malignant hematologic processes.