Cerebral malaria (CM) is a disease of the vascular endothelium caused by Plasmodium falciparum It is characterized by parasite sequestration, inflammatory cytokine production, and vascular leakage. A distinguishing feature of P. falciparum infection is parasite production and secretion of histidine-rich protein II (HRPII). Plasma HRPII is a diagnostic and prognostic marker for falciparum malaria. We demonstrate that disruption of a human cerebral microvascular endothelial barrier by P. falciparum-infected erythrocytes depends on expression of HRPII. Purified recombinant or native HRPII can recapitulate these effects. HRPII action occurs via activation of the inflammasome, resulting in decreased integrity of tight junctions and increased endothelial permeability. We propose that HRPII is a virulence factor that may contribute to cerebral malaria by compromising endothelial barrier integrity within the central nervous system.,Cerebral malaria is a devastating disease. Patients have high levels of the protein HRPII in their blood. We have found that endothelial cell barriers become leaky when treated with concentrations of HRPII similar to those found in patients. This result suggests that HRPII may be important in cerebral malaria. Our finding that HRPII functions by causing inflammation suggests points of intervention for therapy or vaccination against this disease.