We aimed to examine the ability of transplanted mesenchymal stem cells (MSCs) to attenuate cardiac fibrosis caused by global heart failure, and investigate the mechanisms that are possibly mediating this effect. Global heart failure was induced in Wistar rats by isoproterenol injection. Four weeks later, MSCs were transplanted by intramyocardial injection, while control groups were treated by injection of cell culture medium alone. Four weeks after transplantation, heart function was assessed, and histologic and molecular analyses conducted. Compared with the medium-treated group, MSC transplantation significantly decreased the expression of collagens I and III, and matrix metalloproteinase 2 and 9, but heart function was improved in MSC-treated animals. In addition, expression of antifibrotic factor, hepatocyte growth factor (HGF), was detected in cultured MSCs, suggesting a possible mechanism underlying antifibrotic effects. Importantly, HGF expression levels were higher in MSC-treated hearts, compared with medium-treated hearts. Therefore, we could conclude that MSC transplantation can attenuate myocardial fibrosis in a rat model of global heart failure, and this may be at least partially mediated by paracrine signaling from MSCs via antifibrotic factors such as HGF.