In this study, we used a comprehensive, advanced proteomic approach for quantitative and qualitative CSF protein analyses in combination with clinical and radiological assessment of MS patients, demonstrating that intrathecal IgM levels are increased in the CSF of treatment-naive MS patients compared to controls and that there is significant correlation between CSF IgM levels and further CSF molecules related to B-cell, macrophage, and microglia activity. This evidence concerns the gene CSF2 and myeloid sarcoma.