Abstract Body: Cardiac macrophages significantly expand in chronic heart failure (HF). We tested the hypothesis that CD206⁺ macrophages expressing interleukin (IL)-4Ra in the failing heart are key drivers of left ventricular (LV) remodeling and ischemic cardiomyopathy. Cardiac macrophages were profiled using flow cytometry in adult male C57BL/6 (WT) mice following non-reperfused myocardial infarction (MI) to induce HF or sham operation. CD206⁺ macrophages progressively expanded in post-MI hearts during the progression of LV remodeling and comprised ~85% of macrophages at 8 w. These macrophages were exclusively proliferative and predominantly C-C motif chemokine receptor (CCR2)^– and major histocompatibility complex (MHC)II^hi in failing hearts, with the majority (92%) of CD206⁺CCR2^– macrophages expressing LYVE-1, an embryonically-derived resident macrophage marker. Nearly half of cardiac CD206⁺ macrophages expressed IL-4Ra; the abundance of CD206⁺IL-4Ra⁺ directly correlated with LV dysfunction and fibrosis. Intramyocardial adoptive transfer of IL-4-polarized bone marrow derived CD206⁺ macrophages induced progressive LV dilation, dysfunction and fibrosis over 4 w in naïve recipient mice. To evaluate the role of CD206⁺IL-4Ra⁺ macrophages in LV remodeling, we used male and female LysM^CreERT2;IL-4Ra^F/F mice that allow for inducible myeloid-specific IL-4Ra gene deletion. Administration of tamoxifen from at 4 to 10 w post-MI (in established HF), effectively deleted IL-4Ra in cardiac macrophages and significantly reduced CD206⁺ macrophage abundance and proliferation in the remodeling heart. Myeloid-specific IL-4Ra deletion further prevented LV remodeling progression, improved fibrosis and neovascularization, and alleviated LV systolic dysfunction, while suppressing expansion of cardiac immune cells and blood Ly6C^high monocytosis. We conclude that an expanded and proliferative population of CD206⁺IL-4Ra⁺ macrophages primarily derived from resident macrophages are key mediators of pathological LV remodeling and fibrosis. Inhibition of CD206⁺ macrophage IL-4Ra signaling may be a fruitful therapeutic approach to alleviate disease progression in HF.