A new Duffy specificity, Fy6, defined by a murine monoclonal antibody of the IgG1 kappa class, is related to susceptibility to malarial invasion. In humans, Fy6 is present on the red cells of all persons except those of the Fy(a-b-) type, a distribution resembling that of Fy3. However proteolytic enzyme treatment of red cells enhances the reactivity of Fy3, whereas Fy6, like Fya and Fyb, is susceptible to degradation by this process. The number of Fy6 sites on human red cells was found to be 12,200 per cell, in close agreement with earlier estimates of the number of Fya sites. Anti-Fy6 reacted in western blots with a membrane glycoprotein of approximately 46,000 Mr, not significantly different from that of a molecule known to bear the Fya determinant. The Fy6 epitope is shown to be present on the red cells of some but not all nonhuman primate species, where it has a distribution not only distinctly different from Fya, Fyb, and Fy3, but in close accordance with susceptibility to penetration by Plasmodium vivax. Thus, the red cells of two species of macaques (Macaca mulatta and M. fascicularis), which are invaded by Plasmodium knowlesi but not by P. vivax are shown to have other Duffy antigens but to be devoid of Fy6. It appears, therefore, that the red cell epitopes used by these closely related species are distinct, and that susceptibility to P. vivax merozoite penetration is dependent on the presence of Fy6.