The receptor for advanced glycation endproducts (RAGE) contributes to the inflammatory response in several acute and chronic diseases. This has been mostly attributed to its strong activation of NK-kB leading to the upregulation of several proinflammatory cytokines and adhesion molecules. Using intravital microscopy and flow chamber assays, we studied leukocyte rolling in the absence of RAGE. We show in trauma- and TNF-a-stimulated cremaster muscle venules of RAGE-deficient mice that P-selectin-dependent rolling is significantly reduced compared to wild type mice. To dissect, whether the reduction in P-selectin dependent rolling is caused by defective P-selectin ligand activity on leukocytes or due to a functional attenuation of P-selectin activity on the endothelium, we generated bone marrow chimeric mice (RAGE-/- into WT; WT into RAGE-/-). We found normal P-selectin dependent rolling in inflamed cremaster muscle venules of RAGE-/- into WT mice while P-selectin dependent rolling was significantly reduced in WT into RAGE-/- mice. These results suggest that endothelial RAGE controls P-selectin dependent rolling in vivo. Additional experiments using in vitro and ex vivo flow chamber assays, demonstrated normal P-selectin ligand function on leukocytes and also excluded any soluble plasma factors for the observed reduction in P-selectin dependent leukocyte rolling. Taken together, these findings provide strong evidence that endothelium expressed RAGE controls P-selectin dependent rolling during acute inflammation in vivo.