<jats:p> <jats:bold> <jats:italic>Background—</jats:italic> </jats:bold> Despite advances in surgical and percutaneous coronary revascularization, ongoing ischemia that is not amenable to standard revascularization techniques is a major cause of morbidity and mortality. Hepatocyte Growth Factor (HGF) has potent angiogenic and anti-apoptotic activities, and this study evaluated the functional and biochemical effects of HGF gene transfer in a rat model of postinfarction heart failure. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> Lewis rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient recombinant adenovirus encoding HGF (n=10) or empty null virus as control (n=9), and animals were analyzed after six weeks. Pressure-volume conductance catheter measurements demonstrated significantly preserved contractile function in the HGF group compared with Null control animals as measured by maximum developed LV pressure (79±5 versus 56±4 mm Hg, <jats:italic>P</jats:italic> <0.001) and maximum dP/dt (2890±326 versus 1622±159 mm Hg/sec, <jats:italic>P</jats:italic> <0.01). Significant preservation of LV geometry was associated with HGF treatment (LV Diameter HGF 13.1±0.54 versus Null 14.4±0.15 mm <jats:italic>P</jats:italic> <0.01; LV wall thickness 1.73±0.10 versus 1.28±0.07 mm <jats:italic>P</jats:italic> <0.01). Angiogenesis was significantly enhanced in HGF treated animals as measured by both Von Willebrand’s Factor immunohistochemical staining and a microsphere assay. TUNEL analysis revealed a significant reduction in apoptosis in the HGF group (3.42±0.83% versus 8.36±1.16%, <jats:italic>P</jats:italic> <0.01), which correlated with increased Bcl-2 and Bcl-x <jats:sub>L</jats:sub> expression in the HGF animals. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> Hepatocyte Growth Factor gene transfer following a large myocardial infarction results in significantly preserved myocardial function and geometry, and is associated with significant angiogenesis and a reduction in apoptosis. This therapy may be useful as an adjunct or alternative to standard revascularization techniques in patients with ischemic heart failure. </jats:p>