Serum amyloid P-component (SAP) is an acute-phase reactant of mice that occurs at baseline concentrations that vary over a 10-fold range among several common inbred mouse strains. The endogenous SAP levels of all strains increased to 180 to 230 micrograms/ml 24 h after an inflammatory stimulus of either thioglycollate (TG) or lipopolysaccharide (LPS). The C57BL/6J and C57BL/10SN strains displayed 10-fold increases in SAP concentration during acute inflammation, whereas the A/J and DBA/2J strains increased levels by only 20 to 40%. These strains were therefore designated high and low SAP responders, respectively. Testing for H-2 linkage of endogenous SAP levels by using several H-2 congenic lines derived from the C57BL/10, C3H, A, and BALB parental backgrounds indicated that the levels were only weakly influenced by the H-2 complex and were influenced much more strongly by the non-H-2 background genes. F1 hybrids (B6AF1 and B6D2F1) of high and low responder strains displayed a high SAP response similar to that of C57BL/6J mice. Because IL 1-containing macrophage supernatants and semi-purified human IL 1 were previously shown by us to induce SAP in vivo, we titrated IL 1 as LAF activity in supernatants from LPS-activated macrophages from the different mouse strains. Macrophages from the high SAP responder strains displayed significantly higher IL 1 activity than macrophages from the low SAP responder strains. LPS-unresponsive C3H/HeJ or C57BL/10Sc mice did not respond to LPS with an increase in SAP synthesis. Adoptive transfer of the SAP response to C57BL 10Sc mice by using early (90 min) acute-phase sera from the different strains indicated that higher SAP inducer activity was present in the latent phase sera from the high SAP responder strains. The identification of high and low SAP responder strains should aid in determining the biologic role of this acute-phase reactant.