We assessed the effects of genetic ablation of the P-selectin gene in comparison with functional immunoblockade of P-selectin on leukocyte recruitment and the course of disease in dextran sulfate sodium-induced colitis in mice. Compared with control antibody-treated wild-type (WT) mice, WT mice treated with anti-P-selectin antibody and P-selectin^−/− mice had significantly decreased leukocyte rolling and adhesion in colonic venules and reduced clinical and pathological colitis scores. These reductions were more pronounced in anti-P-selectin-treated than in P-selectin^−/− mice. In colonic endothelium, up-regulation of ICAM-1 was similar in WT and P-selectin^−/− mice, but VCAM-1 up-regulation was significantly higher in the latter group. Lung leukocyte infiltration and VCAM-1 expression were increased only in P-selectin^−/− colitic mice. Mortality was observed only in P-selectin^−/− mice. Therefore, ablation of P-selectin function ameliorates colitis, but this protection is attenuated in P-selectin^−/− mice, probably due to compensatory mechanisms that involve up-regulation of other adhesion molecules such as VCAM-1.