Objective The regulation of vascular permeability, leukocyte trafficking, and the integrity of endothelial cell-cell contacts are closely linked by a complex mechanism of inter-regulation. Here we investigate the role of KRIT1, an adherens junction accessory protein required for cell-cell junction stability, in the regulating these vascular functions. Methods and Results Krit1+/− mice exhibited an enhanced edematous response to the complex inflammatory stimuli found in the passive K/BxN model of inflammatory arthritis and the murine air pouch model, yet leukocyte infiltration was unchanged. Correspondingly, reduced KRIT1 expression increased baseline arteriole and venule permeability 2-fold over that of wildtype littermates, as measured by intravital microscopy of the intact cremaster muscle vascular network, but this increase was not accompanied by increased leukocyte extravasation or activation. Direct stimulation with tumor necrosis factor–α induced increased permeability in wildtype mice, but surprisingly, no increase over baseline levels was observed in Krit1+/− mice, despite extensive leukocyte activation. Finally, adoptive transfer of Krit1+/− bone marrow failed to increase permeability in wildtype mice. However, reduced expression of KRIT1 in the hematopoietic lineage dampened the differences observed in baseline permeability. Conclusions Taken together, our data indicate an integral role for KRIT1 in microvessel homeostasis and the vascular response to inflammation.