Humans, apes and Old World monkeys (catarrhines) differ from other mammals in that they do not synthesize alpha-galactosyl epitopes (Gal alpha 1-3Gal beta 1-4GlcNAc-R) on cell surface glycoprotein and glycolipid molecules. In contrast these primates produce large amounts of a natural antibody. anti-Gal, which interacts specifically with alpha-galactosyl epitopes. It is suggested that these differences between catarrhines and other mammals are the result of a major evolutionary selective process which occurred in ancestral Old World primates during the Miocene and which led to the inactivation of the alpha 1,3galactosyl-transferase gene. In New World monkeys, prosimians (lemurs) and non-primate mammals this gene codes for the enzyme synthesizing alpha-galactosyl epitopes. The potential causes for this gene inactivation, the possible relationship of this genetic event to the fossil record and some of the clinical outcomes of this evolutionary event are discussed. (C) 1995 Academic Press Limited