Possible mechanisms of in vivo killing of tumor cells by antibody (Ab) were explored in a model in which Ab suppresses tumor growth in mice. A proportion of tumor cells injected into the peritoneal cavities of complement-deficient A/J mice was lysed within 30 minutes in the presence of anti-tumor cell Ab as demonstrated by the release of 51Cr in vivo. Experiments in which [125I]5-iodo-2'-deoxyuridine-labeled tumor cells were used showed that most tumor cells did not leave the injection site and that lysis occurred inside the peritoneal cavity. In addition, a proportion of the remaining sensitized tumor cells was significantly damaged, as shown by their decreased resistance to osmotic lysis. Morphologic studies ruled out phagocytosis of tumor cells as a mechanism of major significance. Tumor cell damage but not tumor cell lysis could also be induced in vitro with Ab and normal peritoneal cells. These results provided direct evidence of primary cytolysis induced by Ab in vivo, though other concomitant cytotoxic mechanisms may also take place in this model.