Macrophage-stimulating protein (MSP) induces mouse resident peritoneal macrophages to become responsive to the chemoattractant C5a and to ingest C3bi-coated erythrocytes. We now show that MSP action is not limited to complement-induced responses, because it also induced responsiveness to the noncomplement chemoattractant casein. In addition to stimulating responsiveness to attractants, MSP functioned alone as a chemoattractant for resident peritoneal macrophages, with an optimal concentration of approximately 0.2 nM. A critical difference between MSP and C5a is that resident macrophages did not migrate to C5a without an additional stimulus such as MSP in the cell suspension, whereas macrophages suspended in medium alone migrated to MSP in the attractant well. Thus, in contrast to C5a, MSP seems capable of a dual role, both activator and attractant. MSP had no effect on responsiveness of mouse peritoneal exudate macrophages to C5a; nor could it attract exudate macrophages or human blood monocytes. Absorption studies showed that resident macrophages have a receptor for MSP, but exudate macrophages do not. In view of these findings, it seems that the biological role of MSP is not as a recruiter of blood monocytes to sites of inflammation, but as an activator of mature macrophages. The MSP-induced activated state for responsiveness to C5a or C3bi was transient, and decayed at a first order rate with a t 1/2 of approximately 1 h. This is a new example of the transience of activation induced in macrophages by proinflammatory stimuli.