We hypothesized that therapy comprised of anti-apoptotic soluble Fas (sFas) gene transfer combined with administration of the cardioprotective cytokine granulocyte colony-stimulating factor (G-CSF) would markedly mitigate cardiac remodeling and dysfunction following myocardial infarction (MI). On the 3rd day after MI induced by ligating the left coronary artery in mice, 4 different treatments were initiated: saline injection (Group C, n=26); G-CSF administration (Group G, n=27); adenoviral transfer of sFas gene (Group F, n=26); and the latter 2 together (Group G+F, n=26). Four weeks post-MI, Group G+F showed better survival than Group C (96% vs. 65%, p<0.05) and the best cardiac function among the 4 groups. In Group G the infarct scar was smaller and less fibrotic, while in Group F the scar was thicker, without a reduction in area, and contained abundant myofibroblasts and vascular cells; Group G+F showed both phenotypes. G-CSF exerted a beneficial effect on infarct tissue dynamics through antifibrotic and proliferative effects on granulation tissue; however, it also exerts an adverse pro-apoptotic effect that leads to thinning of the infarct scar. sFas appeared to offset the latter drawback. In vitro study using cultured myofibroblasts derived from the infarct tissue revealed that G-CSF increased proliferating activity of those cells accompanying activation of Akt and signal transducer and activator of transcription 3 while accelerated Fas-mediated apoptosis with increasing Bax/Bcl-2 ratio. The results suggest that combined use of G-CSF administration and sFas gene therapy is a potentially powerful tool against post-MI heart failure.