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Distinguishing neurosarcoidosis (NS) from multiple sclerosis (MS) remains challenging and available parameters lack discriminatory power. Comprehensive flow cytometry data of blood and CSF leukocytes of patients with NS (n = 24), MS (n = 49) and idiopathic intracranial hypertension (IIH, n = 52) were analyzed by machine learning algorithms. NS featured a specific immune cell pattern with increased activated CD4+ T cells in CSF and increased plasma cells in blood. Combining blood and CSF parameters improved the differentiation. We thereby identify and independently validate a multi-dimensional model of blood and CSF supporting the difficult differential diagnosis between NS and MS. Blood and CSF of NS patients exhibit adistinct features that allow a predictive model to distinguish NS from MS. Parts of the images have been adapted from Servier Medical Art and from SVG SILH available under Creative Commons Attribution License. Unlabelled Image • Activated CD4+ T cells in CSF and plasma cells in blood are increased in NS compared to MS. • The combination of blood and CSF parameters aids distinguishing between NS and MS. • We generated and validated a multi-dimensional model of blood and CSF parameters to discriminate NS from MS. [ABSTRACT FROM AUTHOR]