A system has been developed in vitro in which human red cells, in the presence of fresh human (or rat) serum, are parasitized by the hemosporidian protozoan Babesia rodhaini. The ability of B. rodhaini to penetrate red cells depends on factors of the alternative complement pathway (properdin and factor B) as well as ionic magnesium and the third (C3) and the fifth (C5) components of complement. These data indicate a novel mechanism by which a parasite is able to utilize the complement system. The data are in accord with and further amplify earlier observations that demonstrated a requirement for complement in the development of babesial infection in rats.