Baló's disease is characterized by alternating rings of demyelination and preserved myelin. As additional multiple sclerosis (MS)-like lesions often coexist in Baló's cases, Baló's disease is regarded as a variant of MS. In demyelinated areas, many hypertrophic astrocytes are present in close contact with oligodendrocytes, which often show apoptotic features. In the outermost layer of preserved myelin, stress proteins involved in tissue preconditioning are abundant in oligodendrocytes. The peri-plaque perimeter is thus assumed resistant to subsequent attack, thereby leaving a layer of preserved myelin. In some cases, Baló's concentric rings develop step by step in a centrifugal direction, whereas many other cases show simultaneous enhancement of multiple rings. Therefore tissue preconditioning and successive ring formation does not fully describe the mechanism of the disease. We recently reported that in four Filipino Baló's patients, aquaporin-4 (AQP4) was extensively lost in glial fibrillary acidic protein-positive hypertrophic astrocytes, both in demyelinated and myelinated layers of all actively demyelinating lesions. None of six further patients with MRI-confirmed Baló's disease were seropositive for anti-AQP4 antibody. I propose that AQP4 astrocytopathy, in the absence of anti-AQP4 antibody, is characteristic of Baló's disease. This hypothesis should be tested in future experimental studies.