There is limited evidence that inhibition of the activity of the protease calpain I reduces inflammation. Here we investigate the effects of calpain inhibitor I in animal models of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis). We report here for the first time that calpain inhibitor I (given at 5, 10, or 20 mg/kg i. It is now widely accepted that the formation of pro-inflammatory cytokines [eg, tumor ecrosis factor-␣ (TNF␣), interleukin IL)Ϫ1, IL-6,or IL-8], the expression on endothelium and neutrophils of adhesion molecules (eg, VCAM-1, ICAM-1), and the overproduction of vasoactive mediators [eg, nitric oxide (NO) by inducible NO synthase (iNOS) or eicosanoids by cyclooxygenase-2 (COX-2)] play important roles in the pathophysiology of inflammation. The expression of inducible genes leading to the formation of these proteins relies on transcription factors, which are controlled by (other) inducible genes and, hence, require de novo protein synthesis or alternatively by so-called primary transcription factors. Among the latter, nuclear factor B (NF-B) has received a considerable amount of attention because of its unique mechanism of activation and its active role in cytoplasmic/nuclear signaling, and its rapid response to pathogenic stimulation of NF-B plays a central role in the regulation of many genes responsible for the generation of mediators or proteins in inflammation. These include the genes for TNF␣, IL-1, IL-6, IL-8, VCAM-1, ICAM-1, iNOS, and COX-2, to name but a few.