There are reports that astrocyte perivascular endfeet are damaged in some cases of multiple sclerosis (MS). This study was designed to determine the origin and outcome of astrocyte damage in acute, resolving, and inactive plaques. Ten acute plaques from 10 early MS cases and 14 plaques of differing histological age from 9 subacute and chronic cases were examined immunohistochemically. Also examined were nonnecrotic early lesions in 3 patients with neuromyelitis optica (NMO). Plaques from 3 MS cases were examined electron microscopically. The edge zones in each of the 10 acute MS lesions revealed a complete loss of astrocyte cell bodies and their pericapillary, perineuronal, and perivascular foot processes. Dendrophagocytosis of degenerate astrocytes was observed. Astrocyte precursors, similar to those that replace destroyed astrocytes in nonnecrotic NMO lesions, were present in areas depleted of astrocytes. Resolving plaques were repopulated initially by stellate astrocytes that stained negatively for the water channel molecule aquaporin4 (AQP4). In older lesions, astrocytes were predominantly AQP4-positive. Loss and recovery of astrocytes in new MS lesions may be as important as myelin loss as a cause of conduction block responsible for symptoms in patients with relapsing and remitting and secondary progressive MS.