We have analyzed the potential of unrestricted somatic stem cells (USSCs) to differentiate into cardiomyocytes in culture and investigated the fate of USSCs after transplantation into rat heart in-vivo. After 7 days of coculture with neonatal rat cardiomyocytes, expression of cardiac specific transcription factors (GATA4 & Nkx2.5) and cardiac markers (TnT & -actinin) were found. FACS showed 43% (n=3) of the cells acquired a cardiac phenotype and some USSCs contracted spontaneously and synchronously. In a next step we delivered eGFP⁺ USSCs transcoronarily into immunosuppressed rat hearts or nude rats via a minimal invasive catheter-based technique. We found 79% (n=4) of the cells deposited in the myocardium 2 hours after transplantation and USSCs adhered to the vascular wall and migration across the endothelial barrier was observed. After 7 days, 19.8 % (n=5) of the transplanted eGFP⁺ USSCs were well integrated into the host myocardium. USSCs were morphologically elongated and expressed cardiac specific markers, while some eGFP⁺ USSCs were stained positive for smooth muscle actin and constituted the vascular wall. In addition, we found some cells stained positive for activated-Caspase 3 (apoptosis) and paralleled by the massive infiltration of CD11b⁺ cells into the myocardium. After 21 days only a small fraction of USSCs were found in the myocardium (0.13%, n=4), however, the remaining cells clearly exhibited morphology that similar to mature cardiomyocytes. In summary, USSCs can differentiate into beating cardiomyocytes, after coronary transplantation in-vivo, however, long term survival of differentiated USSCs was rather low despite a high initial fraction of trapped cells.