Background and objective: ADAMTS13 cleaves von Willebrand factor (VWF), a large multimeric protein that plays an important role in thrombus formation by binding to platelets following vascular injury. Epidemiological studies implicate elevated VWF levels and reduced ADAMTS13 activity in plasma as risk factors for myocardial infarction, but it remains unknown whether the ADAMTS13/VWF axis contributes to myocardial infarction pathogenesis. We tested the hypothesis that ADAMTS13 reduces VWF-mediated myocardial ischemia/reperfusion injury in mice. Methods: Myocardial infarction was induced in male mice (8-10 weeks of age) by ligating the left anterior descending coronary artery for 30 minutes followed by 23.5 hours of reperfusion. The extent of myocardium damage was evaluated by measuring infarct size (%) in 2 mm serial sections stained with 2% triphenyl-2, 3, 4-tetrazolium-chloride. Results: Adamts13 -/- mice had significantly larger infarcts (mean ± SEM: 21.4 ± 1.3%, P <0.05) than WT mice (16.9 ± 1.2%) after myocardial ischemia/reperfusion injury. Adamts13+/- mice, which have a 50% reduction in ADAMTS13 activity, had similar sized infarcts (16.6 ± 1.3%) compared to those in WT mice. Because VWF remains the only known substrate of ADAMTS13 in multiple experimental models, we hypothesized that ADAMTS13 reduces myocardial injury through its proteolytic effect on hyper adhesive ULVWF and /or VWF. To test this hypothesis, we used a VWF-blocking antibody. Interestingly, WT mice treated with the VWF-blocking antibody showed a marked reduction in infarct size (7.9 ± 0.6%, P < 0.001) compared with WT mice treated with control Ig (17.5 ± 1.5 %). Finally, Adamts13 -/- mice treated with the VWF-blocking antibody had infarct sizes (8.0 ± 1.5%) that were similar to those WT mice treated with VWF-blocking antibody, demonstrating that increased infarct size in the Adamts13 -/- mice in this acute myocardial ischemia/reperfusion injury model is VWF-dependent. Conclusion: These findings reveal a new role for anti-thrombotic enzyme ADAMTS13 in reducing VWF-mediated myocardial ischemia/reperfusion injury.