Antibody-coated erythrocytes are lysed by murine C5- whole blood but not by plasma separated from such blood. The lytic activity has been shown to derive from platelets that attach to sensitized cells probably through membrane receptors for C3b. Whole blood or platelet-rich plasma (prp) obtained from mice that have been treated with purified cobra venom factor has little or no activity unless it is fortified with fresh C5- plasma. Lysis is observed only if the reactants are incubated at 37 degrees C and mechanical shaking is practiced, at least intermittently, throughout the period of incubation. Adherence of platelets and subsequent lysis are mediated by antibodies of a variety of immunoglobulin classes, including those that fail to mediate complement-dependent lysis. Platelet-mediated lysis is limited to cells to which the platelets adhere; 51Cr labeled, unsensitized cells that are mixed with prp and sensitized, unlabeled cells do not release 51Cr. Normal murine lymphoid cells and ascites tumor cells of mice, rats, and guinea pigs were apparently unaffected by sensitization and incubation with prp. However, because adherence of platelets to these sensitized cells was not observed, it is not clear whether the cells are resistant to the lytic action of platelets or whether the conditions of incubation were unfavorable for the attachment of platelets to the surfaces of nucleated cells. The significance of the lytic reaction described here is not known but may lie in antibody mediated release of microbicidal substances from platelets.