Objective <p>Progression in multiple sclerosis (MS) often corresponds to irreversible disability in MS patients. Cellular changes in the cerebrospinal fluid (CSF) have provided biomarkers and mechanisms in relapsing-remitting MS (RRMS) but remain understudied in primary and secondary progressive MS (summarized herein as PMS).</p> Methods <p>We combined retrospective flow cytometry of CSF cells from RRMS (<i>n</i> = 169), PMS (<i>n</i> = 56), and non-inflammatory controls (<i>n</i> = 74) with prospective CSF single-cell transcriptomics of 35 individuals (11 controls, 12 RRMS, and 12 PMS) and with confirmatory CSF ELISA. Available CSF single-cell data from age-matched and Alzheimer’s disease (AD) patients served as additional controls.</p> Results <p>Proportions of CD14⁺ monocytes in CSF are increased in PMS and correlated with clinical surrogate markers of progression. Transcriptionally, these monocytes resembled border-associated macrophages (BAM)-like cells with a chronically activated antigen-presenting phenotype. Additionally, these monocytes shared some features with disease-associated microglia/macrophages (DAM), previously identified in neurodegeneration. Induction of DAM-associated molecules, including transcribed and soluble TREM2 (sTREM2), characterized secondary progressive MS (SPMS) and supported its differential diagnosis.</p> Interpretation <p>We thus identified MS stage-specific CSF signatures and shared cellular features of degeneration detectable in CSF of PMS patients.</p> Graphical Abstract <p></p>