Mesenchymal stem cells (MSCs) are reported to be immune privileged. We assessed whether their transplantation (Tx) could create a suppressive microenvironment mitigating rejection of coinjected human embryonic stem cells (hESCs). Three weeks after ligation-induced myocardial infarction, 40 immunocompetent rats received 150 μl of cardiac-specified hESCs (5 × 106), MSCs (5 × 106), hESC + MSC (5 × 106 for each), or control medium. Two months after Tx, left ventricle (LV) function was assessed by echocardiography, and hearts were processed for the detection of human cells by immunostaining and quantitative RT-PCR, patterns of rejection, fibrosis, and angiogenesis. Two months after Tx, LV ejection fraction (LVEF) was significantly higher in the ESC and ESC + MSC groups compared with controls. There were few engrafted cells, which expressed markers of endothelial, smooth muscle, and ventricular cardiac cells, particularly in the MSC group. Hearts of all groups demonstrated a similar infiltration by CD4+ and CD3+ cells but MSC-Tx resulted in a greater infiltration of FoxP3 compared with the control and ESC-alone groups. No teratoma was observed. Thus, cotransplantation of ESCs and MSCs provided better functional preservation compared with single-cell treatment alone. However, there was only modest evidence for an immunosuppressive effect of coinjected MSCs and their beneficial effects seemed rather mediated by trophic effects on the host tissue.