The studies presented here indicate that activation of the complement (C') system by a foreign protein will cause membrane injury and passive lysis of unsensitized erythrocytes present at the time of the reaction. These observations suggest that in addition to the classical antibody-C'-induced cytolysis, there are alternative pathways or mechanisms for activation and participation of the terminal C' components in the production of cell membrane injury. We have shown that a substance derived from cobra venom and eluted from a single protein band on polyacrylamide can promote lysis of unsensitized autologous or heterologous erythrocytes in the presence of fresh guinea pig serum and that this lysis-inducing activity and C'-inhibiting activity appear to reside in the same fractions. The lytic activity is prevented by several agents known to impair classical C'3 activity, but is unaffected by certain procedures which interfere with the function of C' components C'1 and C'2, a suggestion that this reaction involves chiefly C'3-C'9. Further, the cobra venom (CV) factor depletes C' activity in cobra serum, and the CV factor (with its 5S serum cofactor) converts purified C'3 to its inactive form,(1) indicating that the reaction of this complex with the complement system occurs without participation of antibody. Therefore, since the lysis-inducing and C'-inhibiting activity of the CV factor appear to result from similar interactions with the complement system, these observations suggest that cell membrane damage and cell lysis can be accomplished through activation of the complement system by a mechanism involving little or no participation of classical antibody or C' components C'1, 4, or 2.