Rationale: The role of mononuclear phagocytes in chronic heart failure (HF) is unknown.Objective: To comprehensively evaluate monocytes/macrophages and dendritic cells (DCs) in HF and the contribution of the spleen to this network and to cardiac remodeling.Methods and Results: C57Bl/6 mice underwent coronary ligation and were evaluated after 8 weeks in the context of chronic HF. As compared with sham-operated controls, HF mice exhibited: 1) increased pro-inflammatory CD11b+F4/80+CD206– macrophages in the heart and pro-inflammatory CD11b+F4/80+Ly6C/Gr-1hi monocytes in peripheral blood, and a diminished CD11b+F4/80+Ly6C/Gr-1hi monocyte reservoir in the spleen, 2) significantly augmented CD11c+B220– classical DCs (cDCs) and CD11c+/lowB220+ plasmacytoid DCs (pDCs) in both the heart and spleen, increased cDCs in peripheral blood, and increased pDCs in the bone marrow, and 3) profound splenic remodeling with more abundant white pulp follicles, variability of follicular size, and markedly increased size of the marginal zone and germinal centers. Splenectomy in mice with established HF reversed long-term cardiac remodeling. Adoptive transfer of splenocytes from mice with HF, but not from sham-operated mice, induced long-term cardiac dilatation, dysfunction, and fibrosis in normal syngeneic recipient mice. Recipient mice also exhibited monocyte activation and splenic remodeling similar to HF mice.Conclusions: Activation of the mononuclear phagocyte network is central to the progression of cardiac remodeling in HF and heightened antigen processing in the spleen plays a critical role in this process. Splenocytes (presumably splenic monocytes and DCs) promote immune-mediated injurious responses in the failing heart, and retain this immune memory upon adoptive transfer.