Objective: To assess whether any alteration of B-cell subset distribution and/or the cytokine production capacities of B cells could be associated with any stage of MS and could be predictive of MS evolution. Methods: We prospectively enrolled radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), naive patients with relapsing remitting MS (RRMS) of any disease modifying drug, and healthy controls (HCs). Peripheral blood B-cell subset distributions and the interleukin (IL)-6/IL-10–producing B-cell ratio were assessed by flow cytometry to evaluate their proinflammatory and anti-inflammatory functional properties. Results: Twelve RIS, 46 CIS, 31 RRMS patients, and 36 HCs were enrolled. We observed that a high IL-6/IL-10–producing B-cell ratio in patients with RIS/CIS was associated with the evolution of the disease in the short term (6 months). This imbalance in cytokine production was mainly explained by an alteration of the production of IL-10 by B cells, especially for the transitional B-cell subset. In addition, a significant increase in IgD−/CD27− B cells was detected in patients with CIS and RRMS compared with HCs (p = 0.01). Apart from this increase in exhausted B cells, no other variation in B-cell subsets was observed. Conclusions: The association between a high IL-6/IL-10–producing B-cell ratio and the evolution of patients with RIS/CIS suggest a skew of B cells toward proinflammatory properties that might be implicated in the early phases of MS disease.