Methods of preventing and/or treating reperfusion injury are provided. The methods involve administering alpha-2-macroglobulin (A2MG) to a subject with ischemia in one or more tissues or organs, in order to prevent or decrease reperfusion injury when blood flow is restored to the tissues or organs (reperfusion). In some aspects, the patient who is treated has had a heart attack (e.g. acute myocardial infarction, AMI) and the ischemic tissue that is protected from reperfusion injury is heart tissue.