We have previously reported on the augmentation of monoclonal anti-Id antibodies by IL-2 in the therapy of a murine B cell lymphoma. The mechanism of this augmentation was through the expansion by IL-2 of effector cells mediating antibody-dependent cellular cytotoxicity. In this paper we explore the power of IL-2 to enhance anti-Id therapy on larger tumor burdens and at sites distant from the site of injection. The combination treatment was able to induce regression of established 1-cm s.c. tumors associated with microscopic metastatic tumor in lungs, liver, and spleen. Further studies into the mechanism of activity showed that IL-2 was unable to augment in vivo or in vitro tumor lysis by F(ab')2 fragments, thus emphasizing the importance of Fc interactions with antibody-dependent cellular cytotoxicity effector cells. FcR-bearing NK cells were increased in the peritoneum of IL-2-treated mice. The augmented therapeutic effect by the combination treatment was specific for tumor cells expressing the target Id, and non-specific cytotoxicity on Id-negative variants was not seen.