C-reactive protein (CRP) delivered in liposomes [CRP-multilamellar vesicles (MLV)] has been demonstrated to inhibit lung and liver metastases in C57 mice bearing the syngeneic tumors T241 fibrosarcoma and MCA-38 colon carcinoma, respectively. Also peritoneal exudate cells (PEC) from CRP-MLV-treated animals exhibited tumor inhibitory activity in the Winn neutralization assay, and the magnitude of this activity was comparable to that of PEC from muramyl tripeptide (MTP)-MLV-treated mice. The present studies were carried out to compare the mechanisms involved in generation of the tumoricidal effector cell by CRP-MLV and MTP-MLV. The antitumor activity of both CRP-MLV- and MTP-MLV-activated PEC was markedly inhibited by antimacrophage antiserum and complement in the Winn neutralization assay. Also, both activities were unaffected by treatment with anti-immunoglobulin antiserum and complement. However, antitumor activity of CRP-MLV-activated PEC was inhibited by anti-Thy 1.2 and antiasialo Gm 1 antisera in the presence of complement, whereas these reagents had no effect on MTP-MLV-activated PEC. Thus, the antitumor effect of MTP-MLV appears to be mediated principally by macrophages, whereas that of CRP-MLV may also involve other cells bearing T- and/or natural killer-cell markers.