A new cytolytic pathway is described whereby cells sensitized with cytotoxic antibody can be specifically lysed in the complete absence of intact, classical complement pathway function. Evaluation of this model with sera deficient in the 4th (C4), 2nd (C2), and 6th (C6) components of complement has revealed that this new lytic mechanism, termed the C1-bypass activation pathway, is initiated by the antibody-mediated activation of C1. Utilizing components of the previously described alternate complement pathway, this pathway bypasses C4 and C2 to activate the third to ninth components of complement (C3-9) with induction of membrane damage.