BackgroundThere is increasing recognition of the importance of B lymphocytes in the immunopathogenesis of multiple sclerosis (MS), encouraging the evaluation of B cell-associated biomarkers in the cerebrospinal fluid (CSF). We aimed to evaluate the relevance of the B cell chemoattractant CXCL13 as a prognostic marker in patients with clinically isolated syndrome (CIS) regarding conversion to MS, and to compare it to Barkhof criteria in magnetic resonance imaging (MRI), oligoclonal bands (OCB) and the polyspecific intrathecal B cell response against measles, rubella and varicella zoster virus (MRZR).Methodology/Principal FindingsCXCL13 was determined in a prospective study over 2 years including 46 patients that remained CIS over follow-up (CIS-CIS), 45 patients that developed MS (CIS-RRMS), and 30 controls using ELISA. CSF CXCL13 was significantly elevated in CIS-RRMS as compared to CIS-CIS and controls (p<0.001). It was significantly elevated in CIS with OCB (p<0.001), positive MRZR (p = 0.04), and gadolinium enhancement in MRI (p = 0.02) and showed a significant correlation with CSF leukocyte count (p<0.001) and QIgG (p<0.001). CXCL13 showed the best positive predictive value (PPV) of all parameters investigated (70%, 95%-CI: 53–84%), which could be further increased by combination with Barkhof criteria in MRI (80%).Conclusions/SignificanceOur data indicate the relevance of CXCL13 in CIS to predict conversion to MS. It furthermore shows CXCL13 to be an important mediator in the inflammatory cascade associated with the polyspecific intrathecal B cell response that manifests itself in OCB and MRZR.