To document histopathologic evidence on the pathogenic mechanism of human cerebral malaria, we used light microscopy to study brain specimens from 23 patients who died of central nervous system involvement with Plasmodium falciparum. Sequestration of parasitized red blood cells (PRBCs) leading to cerebral capillary clogging was seen. In a few specimens, vascular clogging by PRBCs was associated with margination of mononuclear cells. In others, capillaries were virtually empty and lymphocytes and monocytes were seen in apposition (marginated) to the capillary endothelial surface. The endothelial cells appeared plump, hypertrophied, and prominent. The capillary wall appeared thickened by fibrinous material. Massive intercellular brain edema along with extravasated red blood cells, mononuclear cells, and plasmatic fluid was also noticed. In addition to hypoxia induced by PRBC-mediated vascular clogging, marginating mononuclear cells may contribute to the pathogenesis of cerebral malaria. The precise role played by this phenomenon needs further evaluation.