Multiple sclerosis (MS) is an immune-mediated disease of unknown origin that is overrepresented in females, and involves inflammation in the central nervous system. B cells are a key driver of disease in MS, evidenced by the success of current MS therapies, such as anti-CD20 molecules, which deplete B cells in the circulation. The benefits of these treatments are thought to be attributed to depletion of memory B cells that may harbour self-reactive, but so far unidentified, B cell receptor clones. However, the roles that other B cells play in early disease development are unclear. We investigated B cell subsets in people with early or pre-MS, and found that lower expression of FcγRIIb (CD32b), a regulatory receptor for IgG, is detected on early B cell subsets including naive and marginal zone-like B cells from females1. This implies that early MS pathogenesis may be associated with failure of peripheral B cell tolerance mechanisms. Moreover, lower CD32b expression was associated with evidence of Epstein-Barr Virus (EBV) reactivation, presenting a possible link between the known risk of EBV infection and developing MS. This research provides the first evidence that lower CD32b on B cells, known to be associated with a range of autoimmune diseases, is present in females with early MS.