OBJECTIVE: In this study the ability of unrestricted somatic stem cells (USSC) and mononuclear cord blood cells (MN-CBC) was tested to improve heart function and left ventricular (LV) remodeling after myocardial infarction (MI). METHODS: The cells were delivered by i.v. or intramyocardial injections in rat models of MI by permanent coronary artery occlusion and by ischemia/reperfusion (I/R) injury. Heart function and remodeling was followed by recurrent echocardiography over 8 or 12 weeks after which catheterization was performed. RESULTS: Although injected labeled cells could be observed within the myocardium for up to 6 d, there was no sign of cardiac regeneration 8 or 12 weeks after MI. However, the mRNA expression of components of the extracellular matrix was attenuated in the infarct scar 12 weeks after MI and cell injection. Additionally, the expression of interleukin (IL)-6 but not of IL-1 beta increased at the site of injury and the adjacent border-zone 12 weeks after I/R and USSC-injection. However, these effects did not translate into improved heart function or attenuated LV dilatation. CONCLUSION: These data indicate that cord blood cell implantation after MI acts through paracrine mechanisms to modify remodeling rather than myocyte regeneration. The role of myofibroblasts and the optimal conditions of cell application need to be determined to translate these mechanisms into functional improvement.