Decades of research have examined immune modulatory strategies to protect the heart after an acute myocardial infarction and prevent progression to heart failure, but have failed to translate to clinical benefit. To determine anti-inflammatory actions of apoA-I nanoparticles (n-apoA-I) that contribute to cardiac tissue recovery after myocardial infarction. Using a preclinical mouse model of myocardial infarction, we demonstrate that a single intravenous bolus of n-apoA-I (CSL111, 80mg/kg) delivered immediately after reperfusion, reduced the systemic and cardiac inflammatory response. N-apoA-I treatment lowered the number of circulating leukocytes by 30{plus minus}7% and their recruitment into the ischemic heart by 25{plus minus}10% (all p<5.0E-2). This was associated with a reduction in plasma levels of the clinical biomarker of cardiac injury, cardiac troponin-I by 52{plus minus}17% (p=1.01E-2). N-apoA-I reduced the cardiac expression of chemokines that attract neutrophils and monocytes by 60-80%, and lowered surface expression of integrin CD11b on monocytes by 20{plus minus}5% (all p<5.0E-2). Fluorescently labeled n-apoA-I entered the infarct and peri-infarct regions and co-localized with cardiomyocytes undergoing apoptosis and with leukocytes. We further demonstrate that n-apoA-I binds to neutrophils and monocytes, with preferential binding to the pro-inflammatory monocyte subtype and partially via scavenger receptor BI (SR-BI). In patients with type 2 diabetes mellitus, we also observed that intravenous infusion of the same n-apoA-I (CSL111, 80mg/kg) similarly reduced the level of circulating leukocytes by 12{plus minus}5% (all p<5.0E-2). A single intravenous bolus of n-apoA-I delivered immediately post-myocardial infarction reduced the systemic and cardiac inflammatory response through direct actions on both the ischemic myocardium and leukocytes. These data highlight the anti-inflammatory effects of n-apoA-I and provide preclinical support for investigation of its use for management of acute coronary syndromes in the setting of primary percutaneous coronary interventions.Rationale: