Erythrocyte invasion by the blood-stage Plasmodium falciparum parasites is a multistep process involving specific interactions between parasites and red blood cells. Several proteins are involved in this process, including EBL ligands. The structure of the EBA-140 ligand, a member of the EBL protein family, provides a full description of its molecular interactions with the erythrocyte receptor. The crystal structure of the EBA-140 Region II in a complex with sialolactose revealed that the binding region is monomeric. Two glycan binding pockets, one in each F1 or F2 domain, were identified. Stark differences in the receptor binding for the F1 and F2 domains suggests that each domain performs a distinct function. Although both domains are required for effective glycan binding, it seems that the interaction may be mediated solely by the F1 domain. The structure of the binding region and the interaction with glycan are unique to the EBA-140 ligand and not shared by other EBL ligands. The EBA-140 ligand binds specifically to human erythrocytes through the membrane sialoglycoprotein glycophorin C. The receptor site for the EBA-140 ligand was suggested to be a cluster of N-and O-linked sialylated glycans on the GPC molecule, whose conformation is dependent on the polypeptide chain region composed of amino acid residues 36-63. Precise definition of the binding site for the EBA-140 ligand on glycophorin C may be important with respect to human erythrocyte invasion inhibition strategies based on a receptor.