The binding of antimoesin antibodies from ascites fluids to the surfaces of human and rodent cells was found to parallel the level of CD46 expression. No such reactivity was detected with a purified antimoesin antibody which recognized intracellular moesin. In Western blots, antimoesin antibodies were found to react with solubilized CD46 and a recombinant soluble form of CD46. Antimoesin antibodies also reacted with CD46/CD4 molecules containing only the SCR I and II domains required for measles virus (MV) hemagglutinin binding onto CD46. We suggest that the weak cross-reactivity of antimoesin antibodies with CD46 explains the inhibitory effect of these antibodies on MV entry and that moesin is not directly involved in MV binding.