Microinfarcts are a common clinical feature of the aging brain, particularly in patients with cognitive decline or vascular or Alzheimer's dementia. However, the natural history of these lesions remains largely unexplored. Here we describe a mouse (C57BL/6J) model of multiple diffuse microinfarcts induced by unilateral internal carotid artery injection of cholesterol crystals (40 - 70 mu m). Microinfarcts were spread throughout the deep cortex, subcortical tissue, and hippocampus and were comprised of a core positive for CD68 (a marker for reactive microglia and macrophages), surrounded by large regions of glial fibrillary acidic protein-positive reactive astrogliosis. Widespread reactive gliosis, including mislocalization of the astrocytic water channel aquaporin 4 persisted long after injury, recovering only after 1 month after stroke. Within the cortex, neuronal cell death progressed gradually over the first month, from similar to 35% at 3 d to 60% at 28 d after stroke. Delayed demyelination was also observed in lesions, beginning 28 d after stroke. These findings demonstrate that microinfarct development follows a distinct course compared to larger regional infarcts such as those induced by middle cerebral artery occlusion. The long-lasting gliosis, delayed neuronal loss, and demyelination suggest that the therapeutic window for microinfarcts may be much wider (perhaps days to weeks) than for larger strokes.