The leukocyte integrin LFA‐1 plays an important role in leukocyte trafficking and the immune response. Using LFA‐1‐deficient mice, we demonstrate that LFA‐1 regulates the trafficking of lymphocytes to peripheral lymph nodes, and, to a lesser degree, to mesenteric lymphnodes and acute inflammatory sites. LFA‐1, either because of its role in initial adhesion and/or the passage of leukocytes across endothelial cells, plays a vital role in T lymphocyte and neutrophil transendothelial migration. Neutrophils and activated T lymphocytes from LFA‐1‐deficient mice were unable to cross endothelial cell monolayers in response to a chemokine gradient, whereas wild‐type (WT) T lymphocytes and neutrophils were capable of migration. By contrast, LFA‐1‐deficient T lymphocytes displayed normal chemotaxis to the same chemokine. Our studies with LFA‐1‐deficient monocytes indicate that LFA‐1 acts in concert with complement receptor 3 to mediate transendothelial migration of these cells, as anti‐CD18 monoclonal antibodies (mAb) blocked both WT and LFA‐1‐deficient monocyte transendothelial migration, whereas anti‐CD11b mAb preferentially blocked transendothelial migration of LFA‐1‐deficient monocytes. Finally, whereas anti‐CD31 mAb blocked WT monocyte and neutrophil transendothelial cell migration they did not block LFA‐1‐deficient monocyte and neutrophil transendothelial migration.