The effect of human C-reactive protein incorporated into multilamellar vesicles (CRP-MLV) was studied in assays of macrophage function. Peritoneal exudate macrophages from C57BL/6 mice phagocytosed CRP-MLV in vitro more rapidly than multilamellar vesicles bearing comparable amounts of immunoglobulin G. Exposure of peritoneal exudate macrophages in vitro to CRP-MLV resulted in development of tumoricidal activity against syngeneic T241 fibrosarcoma and B-16 melanoma cells and against allogeneic Sarcoma 1 cells. Peritoneal exudate macrophages obtained from mice given CRP-MLV i.p. demonstrated antitumor activity against the syngeneic T241 fibrosarcoma in a Winn-type assay, and when challenged in vitro with phorbol myristate acetate, they showed elevated superoxide anion production. Administration of CRP-MLV i.p. did not enhance natural killer activity of spleen cells, however. In superoxide anion assays, CRP-MLV were approximately 10 to 100 times more effective than free C-reactive protein. Results indicate that C-reactive protein is capable of activating macrophages, thus supporting the concept of C-reactive protein as an immunomodulator.