Leukocyte recruitment during inflammation follows a well-defined cascade of adhesive events beginning with selectin-mediated capture and rolling followed by chemokine-triggered activation of leukocyte integrins which leads to firm leukocyte adhesion on the endothelium and subsequent transmigration into inflamed tissue. Recently, the FERM domain protein Kindlin-3 has been demonstrated to be required for the activation of b3 integrins on platelets. In addition, mutation in the Kindlin-3 gene was suggested to cause leukocyte adhesion deficiency III (LAD III). To address the role of Kindlin-3 on leukocyte recruitment in vivo, we studied leukocyte rolling, adhesion and extravasation in inflamed cremaster muscle venules in the absence of Kindlin-3. Loss of Kindlin-3 led to a significant increase in the systemic leukocyte count and almost completely abolished firm leukocyte adhesion and extravasation in TNF-a-stimulated cremaster muscle venules. However, selectin-mediated leukocyte capture and rolling were unaffected, which could be confirmed in an ex vivo flow chamber system using immobilized P-selectin. Taken together, we found that Kindlin-3 is essential in mediating b2 (and b1) integrin-dependent leukocyte adhesion and extravasation during inflammation, which is in agreement with the phenotypic changes reported in patients suffering from LAD III.