ABSTRACTLeukocyte recruitment to sites of inflammation requires the functions of selectins and integrins. P‐selectin null (CD62P–/–) mice show a mild and CD18 null (CD18–/–) mice a more severe neutrophil recruitment defect in some inflammatory models. To investigate the possible cooperative interactions between CD18 integrins and P‐selectin in mediating neutrophil recruitment, we generated CD18–/–CD62P–/–double null mice. CD18–/–CD62P–/–mice were apparently normal at weaning and fertile but later failed to gain weight, showed increased susceptibility to infection by fecal and commensal bacteria, and survived only 5–6 months. Some CD18–/–CD62P–/–mice showed severe spontaneous skin lesions; most showed neutrophil infiltration in the lungs and liver, and positive bacterial cultures from internal organs. The number and velocity of rolling leukocytes in tumor necrosis factor a treated venules of CD18–/–CD62P–/–mice was similar to those in wild‐type mice, but neutrophil adhesion was severely reduced. Only 25% of adhered leukocytes were neutrophils in CD18–/–CD62P‐/mice vs. >90% in wild‐type, CD62P–/–, and CD18–/–single mutants. Our data show that removing both P‐selectin and CD18 integrins from mice leads to severe neutrophil recruitment defects and spontaneous pathology.—Forlow, S. B., Foley, P. L., Ley, K. Severely reduced neutrophil adhesion and impaired host defense against fecal and commensal bacteria in CD18–/–P‐selectin–/–double null mice. FASEB J. 16, 1488–1496 (2002)