Complement activation is critical in the development of local mucosal damage and inflammation as well as of remote organ injury after mesenteric ischemia/reperfusion. To further define the role of C5 activation in local and remote tissue injury, C5 deficient (C5(-/-)) and wild-type control (C5(+/+)) mice treated with an anti-C5 mAb were subjected to sham or ischemia followed by up to 4 h of reperfusion. The development of local (intestinal) and remote (lung) injury was associated with the expression of CD49d on the surface of circulating blood neutrophils and with VCAM on the endothelial cells of intestinal and lung vessels. Because CD49d heterodimerizes with integrin beta1 on the surface of neutrophils and can bind VCAM on the endothelium, we propose that complement activation causes organ damage by upregulating molecules that lead to inappropriate homing of neutrophils.