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EDTA chelation therapy has been in off-label use for the treatment of atherosclerosis. We review the results of the first large-scale randomized trial of this treatment.The trial to assess chelation therapy was a $30 million National Institutes of Health-funded study of the safety and efficacy of EDTA-based chelation infusions in 1708 post-myocardial infarction (MI) patients. The trial to assess chelation therapy demonstrated a significant (P = 0.035) 18% reduction in a combined primary endpoint of death, MI, stroke, coronary revascularization, or hospitalization for angina. In diabetic patients the benefit was more extreme, with a 41% relative reduction in risk (P = 0.0002) and a 43% reduction in total mortality (P = 0.011). Safety data were favorable. A reduction of oxidative stress by chelation of toxic metals has been proposed as a possible mechanism of action.Recent research suggests that EDTA chelation may be a well-tolerated and effective treatment for post-MI patients. Future replication and mechanistic studies are important prior to implementation in all post-MI patients.