Objective: Early cell death remains a major limitation of skeletal myoblast transplantation. Because the poor vascularization of the target scars contributes to cell loss, we assessed the effects of combining skeletal myoblast transplantation with administration of hypoxia-inducible factor 1α, a master gene that controls the expression of a wide array of angiogenic factors. Methods: A myocardial infarction was created in 56 rats by means of coronary artery ligation. Eight days later, rats were randomly allocated to receive in-scar injections of culture medium (control animals, n = 11), skeletal myoblasts (5 × 106, n = 13), adenovirus-encoded hypoxia-inducible factor 1α (1.0 × 1010 pfu/mL, n = 7), or skeletal myoblasts (5 × 106) in combination with an empty vector (n = 3) or active hypoxia-inducible factor 1α (1.0 × 10 10 pfu/mL, n = 13). A fifth group (n = 9) underwent a staged approach in which hypoxia-inducible factor 1α (1.0 × 1010 pfu/mL) was injected at the time of infarction, followed 8 days later by skeletal myoblasts (5 × 106). Left ventricular function was assessed echocardiographically before transplantation and 1 month thereafter. Explanted hearts were then processed for the immunohistochemical detection of myotubes, quantification of angiogenesis, myoblast engraftment, and cell survival. Results: Baseline ejection fractions were not significantly different among groups (35%-40%). One month later, ejection fraction had decreased from baseline in control hearts and in those injected with hypoxia-inducible factor 1α. In contrast, it did not deteriorate after injections of skeletal myoblasts alone or combined with either the empty vector or active hypoxia-inducible factor 1α administered sequentially. The most striking change occurred in the skeletal myoblast plus hypoxia-inducible factor 1α combined group in which ejection fraction increased dramatically (by 27%) above baseline levels and was thus markedly higher than in all other groups (P = .0001 and P = .001 vs control animals and animals receiving hypoxia-inducible factor 1α, respectively). Compared with skeletal myoblasts alone, the coadministration of hypoxia-inducible factor 1α resulted in a significantly greater degree of angiogenesis, cell engraftment, and cell survival. Conclusion: Induction of angiogenesis is an effective means of potentiating the functional benefits of myoblast transplantation, and hypoxia-inducible factor 1α can successfully achieve this goal. Copyright © 2005 by The American Association for Thoracic Surgery.