Biopsy specimens from patients with inflammatory bowel disease have demonstrated an up‐regulation of P‐selectin, suggesting a role for P‐selectin in intestinal inflammation. We examined the role of P‐selectin in experimental intestinal inflammation using mice deficient in P‐selectin alone or in combination with either ICAM‐1 or E‐selectin. Colitis was induced using acetic acid or trinitrobenzene sulfonic acid (TNBS). Damage scores and neutrophil infiltration 24 h post acetic acid were not different between wild‐type and P‐selectin‐ or P‐selectin/ICAM‐1‐deficient mice, whereas P/E‐selectin‐deficient mice had enhanced leukocyte recruitment and damage. At 72 h an attenuation in damage scores and a slight decrease in neutrophil infiltration was observed in the P‐ and P/ICAM‐deficient animals. The P/E‐selectin‐deficient mice maintained enhanced leukocyte recruitment and damage. In wild‐type mice P‐selectin expression was elevated 48 and 72 h post acetic acid‐induced inflammation. Surprisingly, P‐selectin or P‐selectin/ICAM‐1 deficiency did not improve the inflammation induced by TNBS over 7 days. In fact, increased mortality was observed. Anti‐adhesion therapy may play only a limited, beneficial role and often a detrimental role in intestinal inflammation. J. Leukoc. Biol. 66: 67–74; 1999.