Serum amyloid P component (SAP) is a major acute-phase reactant in mice. Recently, it was reported that SAP-deficient mice spontaneously developed antinuclear antibodies and severe glomerulonephritis. Because the SA-P-deficient mice we generated display no obvious phenotypic abnormalities, we investigated whether our SAP-deficient mice would also spontaneously develop autoimmune responses. In accordance with the report, our mice produced high titers of antinuclear antibody but did not develop severe glomerulonephritis. On the other hand, it was recently reported that SAP bound to gram-negative bacteria via lipopolysaccharide (LPS) prevented LPS-mediated activation of a classical complement pathway. Thus, we asked if SAP-deficient mice would show altered responses to an intraperitoneal injection of LPS from Salmonella typhimirium. SAP-deficiency did afford resistance to lethality induced by high-dose LPS. Our experiments clearly showed that contrary to documented data, SAP-deficient mice do not develop serious autoimmune disease and we suggest that SAP has a critical role in LPS toxicity.