The major histocompatibility complex (MHC)-F class Ib locus shows a limited polymorphism, and the function of its mainly intracellular protein is not clear. We have identified human leukocyte antigen (HLA)-F orthologous DNA sequences in Pongidae in order to study the MHC-F gene evolution and its products' function. HLA-F orthologous complementary DNA transcripts are found in chimpanzee and in the new primate species studied (bonobo, gorilla and orangutan). Analyses of the predicted amino acid sequences and their comparison with other primate MHC-F proteins show that MHC-F may be a protein with a typical class I structure and that the key residues of the peptide-binding region are highly conserved in MHC-F in all studied primates species. Thus, MHC-F conservation along the primate evolution suggests an important role in cellular physiology. It is possible that the MHC-F protein could be involved, together with MHC-G and MHC-E, in the natural killer cell activity regulation, although rhesus macaque cannot express complete surface MHC-G orthologue molecules.