B cells mediate multiple sclerosis (MS) pathogenesis by mechanisms unrelated to immunoglobulin (Ig). We reported that supernatants (Sup) from cultured B cells from blood of relapsing remitting MS (RRMS) patients, but not normal controls (NC), were cytotoxic to rat oligodendrocytes (OL). We now show that RRMS blood B cells, not stimulated in vitro, secrete factor/s toxic to rat and human neurons. Cytotoxicity is independent of Ig and multiple cytokines, not complement-mediated, and involves apoptosis. The factor/s have an apparent mw of >300kDa. B cells could contribute to damage within the central nervous system by secreting molecules toxic to OL and neurons.