Acute renal failure (ARF) in response to ischemia‐reperfusion is thought to be associated with neutrophil infiltration. Neutrophil recruitment depends on adhesion molecules, including P‐selec‐tin. Our study sought to characterize the role of P‐selectin in ischemia‐reperfusion (I/R)‐induced acute renal failure (ARF). In wild‐type (wt) and P‐selectin‐deficient (P‐/‐) mice (both C57BL/6), ARF was induced by 32 min bilateral renal ischemia, followed by reperfusion (I/R). Wt showed a 12‐ and 20‐fold increase in creatinine at 24 and 48 h after I/R, respectively. Similar changes were seen in blood urea nitrogen (BUN). By contrast, in P–/– creati‐nine and BUN increased only moderately (fourfold over sham). In wt, renal myeloperoxidase activity, indicating neutrophil infiltration, peaked after 24 h (19‐fold over sham). This was significantly attenuated in P–/– (fivefold over sham). Western blot analysis revealed maximum P‐selectin expression 12 h after I/R in wt. Immunostaining detected P‐selectin in glomerular endothelium and in platelets adherent in glomerular and peritubular vessels. Post‐ischemic injection of P‐selectin antibody at 10 min after reperfusion, but not isotype control antibody, protected wt from ARF similar to the protection seen in P –/–. We conclude that blocking P‐selectin even after onset of reperfusion protects mice from I/R‐induced ARF, suggesting potential therapeutic strategies aimed at blocking P‐selectin.—Singbartl, K., Green, S. A., Ley, K. Blocking P‐selectin protects from ischemia/reperfusion‐induced acute renal failure. FASEB J. 14, 48–54(2000)