Significance The CD4 protein of primates has undergone rapid diversification, but the reasons for this remain unknown. Here we show that within-species diversity of the HIV/simian immunodeficiency virus (SIV) envelope (Env) binding (D1) domain is common among African primate species, and that these polymorphisms can inhibit SIV Env-mediated cell entry. Amino acid replacements in the D1 domain changed putative Env contact residues as well as potential N -linked glycosylation sites in many species, with evidence for parallel evolution and trans-specific polymorphism. These data suggest that the primate CD4 receptor is under long-term balancing selection and that this diversification has been the result of a coevolutionary arms race between primate lentiviruses and their hosts.