Treatment of cultured oligodendrocytes (OLGs) with micromolar quantities of myelin basic protein (MBP) caused a rapid, MBP-dose dependent cell death. In contrast, a 72-hr incubation of OLGs with MBP peptides (1–44, 47–87, 88–151, or 152–167) at comparable concentrations had no effect on cell viability. MBP and MBP peptides (1–44 and 88–151) have been shown to interact with ganglioside GM1 (Tzeng et al.: J Neurochem Res: 42:758–767, 1995). This interaction has been reported to increase calcium influx. Therefore, using the fluorescent dye Indo-1 and an ACAS laser cytometer, we examined the level of intracellular calcium in OLGs after MBP treatment. MBP was shown to provoke a rapid, dramatic, and sustained rise of intracellular calcium in most OLGs. The levels of elevated intracellular calcium were sustained and did not return to baseline even after 10 min. This increase of intracellular calcium was suppressed in the presence of EGTA, indicating that the [Ca2+]i rise was due to the entry of extracellular calcium. Incubation of cultured OLGs with MBP peptides (1–44 or 88–151) caused a modest and transitory elevation of intracellular calcium ions in a lower percentage of OLGs. The potent OLG cytotoxicity of intact MBP and the loss of potency after proteolysis raise the possibility that MBP proteolysis during demyelination protects OLGs from death. ©1995 Wiley-Liss, Inc.