Persistent microvascular obstruction (MVO) after successful percutaneous coronary intervention (PCI) in acute ST segment elevation myocardial infarction (STEMI) has been well-described. MVO predicts lack of recovery of left ventricular function and increased mortality. Sonothrombolysis utilizing diagnostic ultrasound induced cavitation of commercially available microbubble contrast has been effective at reducing infarct size and improving left ventricular ejection fraction (LVEF) when performed both pre- and post-PCI. However, the effectiveness of post-PCI sonothrombolysis alone after successful PCI has not been demonstrated. A prospective randomized controlled trial was performed in 50 consecutive consenting patients with anterior STEMI who underwent a continuous microbubble infusion immediately following successful PCI. Intermittent high mechanical index (MI) impulses were applied only in the sonthrombolysis group. Delayed enhancement magnetic resonance imaging (MRI) was performed at 48h and again at 6-8weeks to assess for differences in infarct size, LVEF, and MVO. There were no differences between groups in age, gender, and cardiovascular risk factors. Significant (>2 segments) MVO following successful PCI was observed in 66% of patients. Although sonothrombolysis reduced the extent of MVO acutely, there were no differences in infarct size, LVEF, or extent of MVO by MRI at 48h. Twenty-eight patients returned for a follow up MRI at 6-8weeks. LVEF improved only in the sonothrombolysis group (∆LVEF 7.81±4.57% with sonothrombolysis vs. 1.77±7.02% for low MI only, p=.011). Post-PCI sonothrombolysis had minimal effect on reducing myocardial infarct size but improved left ventricular systolic function in patients with acute anterior wall STEMI.