The contribution of autoantibody-producing plasma cells in multiple sclerosis (MS) remains unclear. Anti-CD20 B cell depletion effectively reduces disease activity in MS patients, but it has a minimal effect on circulating autoantibodies and oligoclonal bands in the cerebrospinal fluid. Recently we reported that MEDI551, an anti-CD19 mAb, therapeutically ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. MEDI551 potently inhibits pathogenic adaptive immune responses, including depleting autoantibody-producing plasma cells. In the present study, we demonstrated that CD19 mAb treatment ameliorates EAE more effectively than does CD20 mAb. Myelin oligodendrocyte glycoprotein–specific Abs and short-lived and long-lived autoantibody-secreting cells were nearly undetectable in the CD19 mAb–treated mice, but they remained detectable in the CD20 mAb–treated mice. Interestingly, residual disease severity in the CD20 mAb–treated animals positively correlated with the frequency of treatment-resistant plasma cells in the bone marrow. Of note, treatment-resistant plasma cells contained a substantial proportion of CD19+ CD20− plasma cells, which would have otherwise been targeted by CD19 mAb. These data suggested that CD19+ CD20− plasma cells spared by anti-CD20 therapy likely contribute to residual EAE severity by producing autoreactive Abs. In patients with MS, we also identified a population of CD19+ CD20− B cells in the cerebrospinal fluid that would be resistant to CD20 mAb treatment.