There is little agreement among neuropathologists regarding the timing and nature of oligodendrocyte loss in multiple sclerosis (MS). This review describes changes that accompany acute oligodendrocyte loss in new lesions. Included is a description of the immunopathology of new lesions in 23 severe early cases selected from a bank of 300 MS autopsies. Oligodendrocytes in prephagocytic lesions exhibit cytopathic changes that include apoptosis of oligodendrocytes immunoreactive for caspase 3, phagocytosis of apoptotic oligodendrocytes, swelling of cells with abnormal nuclei, complement deposition, and lysis. These are nonspecific changes that provide no clue as to the cause of oligodendrocyte injury. Associated changes include the presence of enlarged immunoglobulin (IgG)⁺ microglia and early macrophages, the presence nearby of a focus of inflammatory demyelination, an open blood–brain barrier, and the presence of rare CD8 T cells. Myelin contacted by IgG⁺ macrophages is immunoreactive for complement but not for IgG. It is likely that macrophage activity in evolving white and gray matter plaques is scavenging activity directed at nonvital myelin secondary to oligodendrocytes loss. One feature of MS that is not understood is the extraordinarily close resemblance the disease shows pathologically to neuromyelitis optica (NMO), including that demyelination in both is secondary to a loss of caspase 3‐positive apoptotic oligodendrocytes. These similarities raise the possibility that like NMO, MS is an autoimmune disease in which oligodendrocyte apoptosis is determined by injury to some other glial or mesenchymal component. Ann Neurol 2012;72:18–31