CD18-deficient mice (CD18^–/– mice) have a severe leukocyte recruitment defect in some organs, and no detectable defect in other models. Mice lacking E-selectin (CD62E^–/– mice) have either no defect or a mild defect of neutrophil infiltration, depending on the model. CD18^–/–CD62E^–/–, but not CD18^–/–CD62P^–/–, mice generated by crossbreeding failed to thrive, reaching a maximum body weight of 10–15 grams. To explore the mechanisms underlying reduced viability, we investigated lethally irradiated CD62E^–/– mice that were reconstituted with CD18^–/– bone marrow. These mice, but not single-mutant controls, showed tenfold-increased rolling velocities in a TNF-α–induced model of inflammation. Leukocyte adhesion efficiency in CD18^–/–CD62E^–/– mice was reduced by 95%, and hematopoiesis was drastically altered, including severe bone marrow and blood neutrophilia and elevated G-CSF and GM-CSF levels. The greatly reduced viability of CD18^–/–CD62E^–/– mice appears to result from an inability to mount an adequate inflammatory response. Our data show that cooperation between E-selectin and CD18 integrins is necessary for neutrophil recruitment and that alternative adhesion pathways cannot compensate for the loss of these molecules.