During the initial phase of the inflammatory response, leukocytes marginate and roll along the endothelial surface, a process mediated largely by the selectins and their ligands. Mice with mutations in individual selectins show no spontaneous disease and have mild or negligible deficiencies of inflammatory responses. In contrast, we find that mice with null mutations in both endothelial selectins (P and E) develop a phenotype of leukocyte adhesion deficiency characterized by mucocutaneous infections, plasma cell proliferation, hypergammaglobulinemia, severe deficiencies of leukocyte rolling in cremaster venules with or without addition of TNF-alpha, and an absence of neutrophil emigration at 4 h in response to intraperitoneal Streptococcus pneumoniae peritonitis. These mice provide strong evidence for the functional importance of selectins in vivo.