We describe the phenotype of mice lacking both endothelial selectins after sequential ablation of the genes encoding P- and E-selectins. In contrast with the rather mild phenotypes observed in mice deficient in a single selectin gene, the doubly deficient mice present extreme leukocytosis, elevated cytokine levels, and alterations in hematopoiesis. Granulocytopoiesis is increased both in bone marrow and spleen, while erythropoiesis is partially translocated to the spleen. Virtual lack of leukocyte rolling and low extravasation at sites of inflammation make these animals susceptible to opportunistic bacterial infections, to which they succumb. Our results show that the absence of endothelial selectins severely affects leukocyte homeostasis and indicate that these two selectins are as important for normal leukocyte function as are the leukocyte β2 integrins.