Activation of the complement cascade is central to many types of injury. Ischemia-reperfusion is an important example of such an event. Using intestinal ischemia-reperfusion as a model, we have further elucidated the importance and mechanism of this activation. Of novel importance is the evidence that natural antibody is a trigger for these events via recognition of self-antigen. In this article, we review the role of natural antibody and complement in intestinal ischemia-reperfusion injury. It is hoped that this study will ultimately lead to better understanding of these important modulators and their role in this type of injury.