A new mechanism of ischemia/reperfusion (I/R) injury is discovered recently operating through innate autoimmunity. Studies of different animal I/R models showed that reperfusion of ischemic tissues elicits an acute inflammatory response involving complement system which is activated by autoreactive natural IgM. Whether similar mechanism operating in human is still unknown. We investigated this important question by testing if human natural IgM could induce I/R injury in an established murine intestinal model. RAG-1^−/− mice (immunoglobulin deficient), which are protected from I/R injury, were reconstituted with purified normal human IgM and subjected in an intestinal injury model. Reconstituted RAG-1^−/− mice that were underwent sham treatment did not show tissue injury in intestine. In contrast, reconstituted RAG-1^−/− mice that underwent 40min intestinal ischemia and 3h reperfusion showed significant injury in the local tissues. In addition, immunohistochemistry showed that complement C4 were deposited in intestinal villi of I/R but not sham treated mice. Therefore, our study is the first report describing that human natural IgM is capable to induce I/R injury in the intestinal model, and further suggests that innate autoimmunity may operate under pathogenic conditions in human.