As opposed to chronic ischemic heart failure (HF), spleen-derived macrophages (Mf) are not prominent disease mediators during the chronic stages of pressure-overload (PO) HF. Increases in Mf during the early stages of PO, however, may serve as important drivers of both remodeling and activation of T-cell responses during later stages. Additionally, recent evidence indicates distinct groups of resident and circulating monocyte-derived infiltrating Mf that have different reparative vis-à-vis pro-inflammatory capacities. We hypothesized that cardiac Mf are expanded during the early stages of PO, primarily due to an increase in infiltrating Mf, and contribute to long-term T-cell activation in the PO heart. Cardiac Mf were characterized by flow cytometry as MerTK+CD64+F480+MHCII+ cells, with infiltrating Mf populations identified as expressing chemokine receptor 2 (CCR2). One week after transverse aortic constriction (TAC), C57Bl/6 mice exhibited significant (p < 0.05) hypertrophy (heart weight/body weight 7.7 ± 0.5 vs 5.7 ± 0.2 mg/g; LV wall thickness 0.84 ± 0.03 vs 0.74 ± 0.02), without change in LVEF as compared with sham. There were robust increases in cardiac macrophages (3.15 ± 0.64 vs 1.09 ± 0.24%), specifically in the infiltrating CCR2+MHCIIhi population (1.6 ± 0.5 vs 0.5 ± 0.1%). TAC mice also exhibited higher circulating Gr1–CD11b+Ly6Chi monocytes (2.6 ± 0.5 vs 1.3 ± 0.2%) that are recruited to tissue via CCR2. To determine activation of the adaptive immune response, we analyzed the mediastinal heart draining lymph nodes (MLN) for T-cells and antigen presenting cells. As compared with sham mice, the MLN of TAC mice were larger with greater cellularity (10.8 x 105 vs 4.2 x 105), especially related to MerTK+CD169+ Mf and CD3+CD8+ T cells. We conclude that there is both an organ-specific and systemic immune response during compensatory PO hypertrophy, despite the absence of ischemic tissue injury. As infiltrating Mf are known to be less reparative, potently pro-inflammatory, and robust activators of adaptive immune cells, specifically targeting Ly6Chi monocyte recruitment and CCR2+ infiltrating Mf during the early compensated stages of pressure-overload may prevent subsequent inflammatory activation, adverse remodeling, and the transition to HF.Author Disclosures: B. Patel: None. M.A. Ismahil: None. S.S. Bansal: None. A. Michaud: None. S.D. Prabhu: None.