Ischemia/reperfusion-induced tissue damage is a significant problem occurring in multiple clinical conditions. Antibodies and complement activation contribute significantly to this pathology. Mice deficient in complement receptors 1 and 2 fail to produce a component of the natural antibody repertoire that binds to ischemia-conditioned tissues and activate complement. In contrast, mice prone to autoimmunity display accelerated tissue injury that results from the binding of autoantibodies to injured tissues. The specificity and production of natural antibodies, their role in autoimmunity and the mode of complement activation are reviewed from the perspective of the processes involved in ischemia/reperfusion-induced tissue damage.