Background: Transendothelial migration of circulating leukocytes into the colonic wall is a key step in the development of the inflammatory infiltrate in IBD. The cell adhesion molecule PECAM-1 (CD31) is expressed in the tight junction area of endothelial cells, where it is supposed to support the transmigration process. The aim of this study was to determine the role of PECAM-1 in experimental IBD and to show whether blockade of PECAM-1 has therapeutic effects. Methods: Chronic colitis was induced in female balb/c mice by cyclic oral administration of dextran sodium sulfate (DSS) 3% (wt/v). Expression of PECAM-1 was visualized by immunohistochemistry. In the treatment group animals received 1 mg/kg anti-PECAM-1 (2H8) i.p. daily starting on day 26. On day 30 leukocyte adhesion and migration was measured during N2O/isoflurane anaesthesia in the distal colon by intravital microscopy. Disease Activity Index (DAI), histology, and MPO-levels were compared to healthy and diseased controls. Results: PECAM-1 was expressed in colitic mice. Chronic DSS colitis was characterized by a marked increase in rolling, adherent and transmigrated leukocytes compared to healthy controls. Immunoblockade of PECAM-1 reduced leukocyte transmigration, rolling and sticking significantly. It also resulted in a significantly diminished DAI and MPO-levels, as well as an amelioration of the histological inflammation score. Conclusions: PECAM-1 plays an important role in transendothelial leukocyte migration in DSS colitis. PECAM-1 could be a novel target for antibody based treatment in IBD.