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The intercellular adhesion molecule-l (ICAM-1, CD54) is one of three putative endothelial receptors that mediate in vitro cytoadherence of P. falciparum-infected erythrocytes. Since cytoadherence to postcapillary venular endothellum is thought to be a major factor in the virulence of P. falciparum malaria, we have examined the interaction between ICAM-and the P. falciparum-Infected cell, and have compared it with the interaction to the physiological counter receptor, the leukocyte integrin LFA-1. Our resultsdemonstrate that the malaria-binding site resides In the first two domains of the ICAM-molecule and overlaps, but is distinct from, the LFA-1 site.