In humans, CD46 has been detected on the acrosomal membrane in sperm, in contrast to widespread surface expression on somatic cells where it plays a key role in the protection from complement attack. In rodents, CD46 is expressed solely on the acrosomal membrane of mature sperm and their immediate precursors, spermatids. A monoclonal antibody against the short consensus repeat (SCR1) ectodomain of CD46 blocks binding of human sperm to zona-free oocytes in vitro. However, CD46-knockout mice are fertile and have an accelerated spontaneous acrosome reaction. Wild-caught field mice (Apodemus) also exhibit a rapid acrosome reaction and CD46 is not expressed in Apodemus sperm. CD46 may, therefore, play a role in stabilization of the acrosomal membrane. Two other complement regulatory proteins, CD55 and CD59, are localized on the plasma membrane of mammalian sperm. In human sperm, CD55 and CD59 are expressed also on the inner acrosomal membrane. It remains to be clarified what is the role of CD46, CD55 and CD59 during fertilization and what are the advantages of not expressing CD46 in field mice sperm.