Background: We hypothesized that pretreatment of an infarcted heart by mechanical transmyocardial revascularization (TMR) prior to transplantation of bone marrow cells (BMC) or BMC expressing angiogenic growth factors would increase transplanted BMC survival and enhance myocardial repair. Methods and Results: Female Lewis rats underwent coronary ligation 3 weeks before creation of 10 needle TMR channels (3 groups), or no TMR (3 groups), and transplantation of 3x10⁶ male donor BMC, BMC transfected with vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and insulin-like growth factor-1 (IGF-1) (BMC+VBI), or medium alone. At 1, 3 and 7 days, we evaluated transplanted cell survival, vascular densities and LV function (N=4 per group x 6 groups x 3 timepoints). At 3 days, vascular densities in the scar were increased by TMR+BMC+VBI and by BMC+VBI (P<0.05), and at 7 days vascular densities were greatest in rats receiving TMR+BMC+VBI (P<0.05). Transplanted cell survival at 3 and 7 days was increased by TMR and by BMC+VBI). Combined therapy with TMR+BMC+VBI resulted in the greatest cell survival at 3 days (P<0.05 vs. BMC. After 7 days, LVEF was lowest in rats receiving neither BMC or TMR, and greatest in rats receiving TMR+BMC+VBI (P=0.004). Conclusions: Mechanical pretreatment of infarcted myocardium by TMR enhances the effect of subsequent cell-based gene therapy on transplanted cell survival, angiogenesis and left ventricular function. Scar pretreatment with TMR combined with cell-based multigene therapy may maximize myocardial repair.