Hippocampal sclerosis (HS) is a pathologic term used to describe severe loss of neurons and reactive gliosis without cystic cavitation in the CA1 sector of the hippocampus. In late life, HS is associated with hippocampal atrophy, severe amnesia, and slowly progressive dementia without clinical seizure activity. HS is difficult to distinguish clinically from Alzheimer's disease and is often diagnosed postmortem. In autopsy series, HS may be found without significant other pathology (2%-4% of cases), but it occurs frequently in combination with other vascular and neurodegenerative disorders (12%-20% of cases). HS is found bilaterally in 50% of cases and unilaterally in 50% of cases, with similar predilection for the right versus left hemisphere. The pathogenesis of HS is unknown and may be multifactorial in origin, possibly due to anoxic/ischemic injury or TDP-43-related neurodegeneration. Little is known about the prevention and treatment of late-life HS, although circumstantial evidence suggests the importance of identifying and treating vascular risk factors.