After myocardial infarction (MI), mononuclear phagocytes infiltrate the heart to orchestrate wound healing. The spleen is considered to be one reservoir for infiltrating immune cells. In chronic heart failure (HF), mononuclear splenocytes are pathologically activated and pro-inflammatory; however, their precise role in early post-MI healing is unclear. We hypothesized that the spleen is necessary for efficient tissue repair after MI, thereby limiting long-term pathological remodeling. Survival or sham splenectomy (Spx or nSpx) were performed in adult CD45.2 C57Bl/6 mice. One month later, Spx and nSpx control mice were subjected to left coronary ligation or sham operation (n=5-10/group), and post-MI remodeling was assessed at 24 h, 10 d, and 8 w. As compared with nSpx sham at 8 w, nSpx MI hearts exhibited significant (p < 0.01): 1) LV dilatation (EDV 112 ± 20 vs 50 ± 6 μL), 2) systolic dysfunction (EF 39 ± 25 vs 63 ± 12%); and 3) hypertrophy (LV/tibia length 10.6 ± 0.7 vs 7.7 ± 0.3 mg/mm). In contrast, as compared with nSpx MI, Spx MI hearts exhibited significant worsening (p < 0.05) of: 1) LV dilatation (EDV 163 ± 80 μL); 2) systolic dysfunction (EF 21 ± 10%); 3) hypertrophy (LV/tibia length 13.3 ± 0.8 mg/mm); 4) ~2-fold decrease in border zone (BZ) neovasculature by isolectin B4 staining; and 5) significantly reduced anti-inflammatory CD206+iNOS– BZ macrophages by immunostaining. Moreover, as compared with nSpx hearts 24 h post-MI, the infarct zone (IZ) of Spx MI hearts exhibited significant decreases in the subset of Tim4+ macrophages, which are primary mediators of apoptotic cell efferocytosis. Notably, Tim4+ macrophage levels in Spx MI hearts were restored upon adoptive transfer of mononuclear splenocytes from CD45.1 syngeneic mice 6 h post-MI. Lastly, at 10 d post-MI, as compared with nSpx, Spx MI hearts revealed reduced MMP9 activation, collagen deposition, and CD206+iNOS– macrophages in the IZ by immunostaining. Hence, we conclude that splenocytes regulate apoptotic cell clearance, tissue neovascularization, and wound healing after MI. Unlike chronic ischemic HF, where mononuclear splenocytes are pro-inflammatory and tissue-injurious, the cardiosplenic axis early after MI is necessary for wound repair and cardioprotective against adverse LV remodeling.Author Disclosures: M. Mohamed Ismahil: None. B. Patel: None. S.S. Bansal: None. T. Hamid: None. M. Goel: None. H. Zhong: None. G. Zhou: None. A.M. Michaud: None. S.D. Prabhu: None.