Complement activation contributes to the expression of local and remote organ injury in animal models of ischemia-reperfusion (IR). We demonstrate here that a soluble form of decay-accelerating factor (DAF) protects normal C57Bl/6 and autoimmunity-prone B6.MRL/lpr mice subjected to hindlimb IR from remote intestinal and lung injury without affecting the degree of local skeletal muscle injury. In addition, DAF treatment attenuates remote organ injury in mice subjected to mesenteric IR. Soluble DAF allowed the deposition of complement 3 in local and remote injury sites while it limited the presence of terminal membrane attack complex and did not increase animal susceptibility to sepsis. These data provide evidence that soluble DAF might offer clinical benefit to patients suffering remote intestinal or lung damage in response to muscle or other organ injury.