Cytoadherence of HB3 and FC27 strains of Plasmodium falciparum-parasitized red blood cells (PRBC) was studied under shear conditions to elucidate the pathways of adherence to microvascular endothelial cells (MEC). HB3 PRBC bound exclusively to MEC CD36 and intercellular adhesion molecule-l (ICAM-1) receptors. FC27 PRBC bound to CD36 and another unidentified pathway but not to ICAM-1. Down-regulation ofCD36 and ICAM-1 expression by phorbol 12,13-dibutyrate abolished HB3 PRBC adherence. Selective up-regulation of CD36 with interferon-γ (IFN-γ) increased PRBC adherence. Conversely, selective up-regulation of ICAM-1 with tumor necrosis factor did not elevate cytoadherence. These data have defined the relative contributions of both CD36 and ICAM-1 to PRBC binding to MEC and have provided evidence for the presence of a novel adhesion mechanism. Furthermore, in addition to antibody blocking of cell adhesion molecules, anti-IfN-γ antibody therapy or pharmacologic manipulation of endothelial cell receptor expression may reduce PRBC sequestration and ameliorate the events associated with human cerebral malaria. © 1993 by The University of Chicago.