The malaria parasite, Plasmodium falciparum, invades the human erythrocyte through a complex interaction with erythrocyte receptors characterized by patterns of resistance to various enzymes. As invasion rates are influenced by blood group polymorphisms, we reasoned that the extremely rare rhesus null (Rh(null)) erythrocytes could be informative in characterizing receptors. The aim was to test whether the complete absence of the Rh complex from the cell membrane impacted on parasite invasion. Enzyme treatment patterns for four P. falciparum isolates were first characterised for normal Rh cells. Two isolates showed an enzyme treatment pattern not hitherto described, with resistance to neuraminidase, trypsin and chymotrypsin. In contrast, all isolates had enhanced invasion rates for the Rh(null) cell for all enzyme treatment regimens. The first finding suggests there is another pathway that P. falciparum can utilise to invade the host. We speculate that the Rh null cell membrane exposes a novel ligand defined as Receptor N.