Mesenchymal stem cells (MSCs) exert therapeutic effects on treating acute myocardial infarction (AMI). Angiogenesis in ischemic heart can promote the supply of oxygen and nutrients to both ischemic myocardium and transplanted stem cells. Focus is then given to the evolving strategies amied at angiogenesis. ILK has been reported to be an important factor regulating apoptosis and angiogenesis. This study examined the role and mechanism of ILK in MSCs survival and angiogenesis. In hypoxic condition, upregulation of ILK expression increased the phosphorylation of Akt and mTOR, resulting in markedly enchanced MSCs survival and VEGF expression; while significantly inhibited MSCs survival and VEGF expression was detected in MSCs with ILK kinase inactivation, which was associated with a reduction of phosphorylation of Akt and mTOR. In addition, it also caused an inhibitory effects of ILK on MSCs survival and VEGF expression, which was abolished by Akt or mTOR inhibitor. Furthermore, it was observed that ILK-overexpressed MSCs increased MSCs survival at 4days and angiogenesis at 3 weeks after transplantation into infracted myocardium as compared with GFP-MSCs group and ILK-SiRNA-MSCs group. This enhanced response was associated with attenuated left ventricular (LV) chamber dilation, reduced LV fibrosis, decreased infarct size and improved LV function. These findings reveal ILK play a pivotal role in regulating MSCs survival and VEGF expression partially through Akt and mTOR signaling pathway. In addition, transplantation of ILK-overexpressed MSCs into infracted myocardium resulted in reduced fibrosis, improved cardiac function and remodeling, which mainly medicated through increased MSCs survival and angiogenesis.