Lysophosphatidic acid (LPA), as an endogenous lipid mediator, has been revealed to regulate many important biological and pathophysiological processes via specific G-protein-coupled receptors termed LPA1-5. We have previously shown that LPA antagonized the apoptosis of mesenchymal stem cells (MSCs) induced by hypoxia and serum deprivation (hypoxia/SD), mimicking ischemic myocardium microenvironment. Whether LPA has the same potentially beneficial effect on MSCs in vivo is unknown. Here we demonstrated that LPA treatment improved graft MSC survival in ischemic myocardium assessed in a gender-mismatched transplantation model by real-time PCR, as well as by TUNEL assay. Moreover, transplantation of LPA-treated MSCs enhanced capillary density determined by immunostaining for platelet endothelial cell adhesion molecule (PECAM)-1, and it is also found that LPA enhanced vascular endothelial growth factor (VEGF) release from MSCs under hypoxia/SD in vitro. We did not get any improvement in left ventricular (LV) function at 1 week after transplantation of LPA-treated MSCs. These data suggest that LPA exerts both protective actions on MSC survival and enhancement on MSC paracrine in vivo and may represent a novel and effective treatment strategy in cell transplantation.