Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation. Recent studies on new functions of SLPI have demonstrated that SLPI may play a larger role in innate immunity than merely as a protease inhibitor. To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI^−/− mice) and analyzed their response to experimental endotoxin shock induced by lipopolysaccharide (LPS). SLPI^−/− mice showed a higher mortality from endotoxin shock than did wild type mice. This may be explained in part by our observation that SLPI^−/− macro-phages show higher interleukin 6 and high-mobility group (HMG)-1 production and nuclear factor κB activities after LPS treatment than do SLPI^+/+ macrophages. SLPI also affects B cell function. SLPI^−/− B cells show more proliferation and IgM production after LPS treatment than SLPI^+/+ B cells. Our results suggest that SLPI attenuates excessive inflammatory responses and thus assures balanced functioning of innate immunity.