The response of neonatal rat oligodendrocytes to contact with myelin extracts prepared from the central and peripheral nervous system was examined. Contact with either CNS myelin or PNS myelin resulted in collapse of the fine structure of the leading edge of oligodendrocytes in vitro. The collapse of the fine structure of oligodendrocyte processes was preceded by a substantial (approximately fivefold) increase in intracellular free calcium concentration. The calcium concentration increase was due, at least in part, to a release of calcium from internal stores, since it persisted when extracellular calcium was removed by chelation with EGTA. The increase in calcium concentration and the coincident morphological change suggest that oligodendrocytes might be able to recognize and react to specific molecules on the surface of other oligodendrocytes.