The acute phase reactant of mice, serum amyloid P-component (SAP), was purified and separated from C-reactive protein (CRP). The purified SAP is composed of identical M, 31 Kd polypeptide subunits, determined by SDS-PAGE. SAP levels increased five-fold by 24 hr after challenge with lipopolysaccharide (LPS) or thioglycollate. This response closely correlated with blood monocytosis and required new macromolecule (protein + RNA) synthesis and secretion by the liver. The induction of the SAP response was adoptively transferred by a serum factor produced in optimal concentrations only 90 min after an inflammatory stimulus, which preceded a detectable increase in SAP. A potent SAP inducer was identified in culture supernatants of LPS-activated macrophages. The rapid induction of SAP synthesis in LPS-unresponsive C3H/HeJ mice was dependent on the amount of lymphocyte-activating factor, LAF(IL 1), present in the macrophage culture supernatants. Partially purified human IL 1 also induced a rapid increase in SAP. Thus the induction of SAP in mice appears to be mediated by a product of macrophages, a cell population that is also expanded as part of the systemic inflammatory response.