Objective(s): Even though the mechanism is not clearly understood, direct intramyocardial cell transplantation has demonstrated potential to treat patients with severe heart failure. We previously reported on the bioengineering of myoblast-based constructs. We investigate here the functional outcome of infarcted hearts treated by implantation of myoblast-seeded scaffolds. Methods: Adult Lewis rats with echocardiography-confirmed postinfarction reduced ejection fraction (48.3% ± 1.1%) were randomized to (1) implantation of myoblast-seeded polyurethane patches at the site of infarction (PU-MyoB, n = 11), (2) implantation of nonseeded polyurethane patches (PU, n = 11), (3) sham operation (Sham, n = 12), and (4) direct intramyocardial myoblast injection (MyoB, n = 11). Four weeks later, the functional assessment by echocardiography was repeated, and we additionally performed left ventricular catheterization plus histologic studies. Results: The ejection fraction significantly decreased in the PU (39.1% ± 2.3%; P = .02) and Sham (39.9% ± 3.5%; P = .04) groups, whereas it remained stable in the PU-MyoB (48.4% ± 3.1%) and MyoB (47.9% ± 3.0%) groups during the observation time. Similarly, left ventricular contractility was significantly higher in groups PU-MyoB (4960 ± 266 mm Hg/s) and MyoB (4748 ± 304 mm Hg/s) than in groups PU (3909 ± 248 mm Hg/s, P = .01) and Sham (4028 ± 199 mm Hg/s, P = .01). Immunohistology identified a high density of myoblasts within the seeded scaffolds without any migration toward the host cardiac tissue and no evidence of cardiac cell differentiation. Conclusions: Myoblast-seeded polyurethane scaffolds prevent post-myocardial infarction progression toward heart failure as efficiently as direct intramyocardial injection. The immunohistologic analysis suggests that an indirect mechanism, potentially a paracrine effect, may be assumed. © 2006 The American Association for Thoracic Surgery.