Cell-based therapy is a promising option for treatment of cardiovascular diseases. Based on experimental studies demonstrating that bone marrow-derived mononuclear cells (BMMNCs) improve the functional recovery after ischemia, clinical trials were initiated to address this new therapeutic concept. BMMNCs improve neovascularization of ischemic tissue by a broad repertoire of potential therapeutic actions. Whereas initial studies documented that the cells incorporate and differentiate to cardiovascular cells, other studies suggested that short-time paracrine mechanisms mediate the beneficial effects. Here, we hypothesized that BMMNCs have a phagocytic ability, and switch to a proangiogenic phenotype after engulfment of apoptotic cells. Activation of such angiogenic program may be pivotal in the beneficial effect of BMMNCs-based therapy. In vitro, wildtype (WT) BMMNCs ingestion of apoptotic cells upregulated the release of proangiogenic factors VEGF and HGF by 15- and 5-fold, respectively. In contrast, BMMNCs collected from mice deficient in MFG-E8, a protein that is required for attachment and engulfment of apoptotic cells by phagocytes, displayed lower phagocytic ability, leading to decrease in VEGF and HGF release. The capacity of BMMNCs to differentiate into cells with endothelial phenotype was similar in control and MFG-E8-deficient cells. In an in vivo model of mice myocardial infaction (MI), transplantation of WT BMMNCs increased fractionnal shortening (120 % of untreated control, p<0.05), 14 days after MI. Size of the infarct scar was reduced by 30 % (p<0.05 vs untreated control), and capillary density in the infarct border zone was raised by 10 % (p<0.05 vs untreated control) in the WT BMMNCs group. In contrast, transplantation of MFG-E8 deficient BMMNCs displayed no significant effect on cardiac function, infarct size or angiogenesis in the ischemic myocardium. Four days after MI, VEGF protein levels were raised by 1.4 fold in the myocardium of WT BMMNCs treated animals compared to untreated controls (p<0.05), while treatment with MFG-E8 deficient BMMNCs failed to raise VEGF levels. Taken together, these results suggest that phagocytosis of apoptotic cells reprograms BMMNCs into a proangiogenic phenotype. Hence, the therapeutic effect of transplanted BMMNCs depends, at least in part, on their phagocytic ability.