Monoclonal antibodies obtained after immunization of mice with human C5 were screened for activity against native C5 and SC5b-9. Clone 568 reacted with the C5 beta-chain in western blotting and with purified native C5 in double antibody enzyme immunoassays. The reactivity of clone 568 against serum decreased markedly when serum was activated with zymosan. The residual activity was found to be against free C5, whereas the antibody did not react at all with the SC5b-9 complex. Thus, the antibody 568 reacts with an activation-dependent C5 epitope, which is concealed when C5 is incorporated into the terminal complement complex.