Background: Multiple needle-based injections of cells in the myocardium are associated with a low engraftment rate, which may limit the benefits of the procedure. This study used skeletal myoblasts to perform a head-to-head comparison of conventional injections with epicardial deposition of scaffold-embedded cells. Methods: Four weeks after ligation-induced myocardial infarction, 40 rats were randomly allocated to receive intramyocardial injections of 5 million human skeletal myoblasts or control medium or to have the infarcted area covered with either a bilayer myoblast cell sheet prepared from a fibrin-coated culture plate or a myoblast-seeded collagen sponge (Gelfoam; Pharmacia & Upjohn, Kalamazoo, MI). End points, assessed after 1 month, included left ventricular function blindly measured by echocardiography, quantification of cell engraftment by quantitative real-time polymerase chain reaction and immunostaining, histologic assessment of fibrosis and angiogenesis, and tissue levels of host-specific angiogenic and antifibrotic cytokines. Results: Compared with control medium- or myoblast-injected hearts, those receiving the two cell constructs demonstrated the highest recoveries of left ventricular function (p = 0.004 versus controls). Both myoblast cell sheets and myoblast-seeded Gelfoam sponges also resulted in significantly greater angiogenesis compared with controls. The Gelfoam group was associated with the best outcome with regard to the number of engrafted donor cells (p = 0.03 versus myoblasts) and the reduction of fibrosis (p = 0.02 and p = 0.04 versus the control and myoblast groups, respectively). Conclusions: Compared with injections, delivery of myoblasts in a construct overlaying the infarcted area is associated with better graft functionality, possibly because of maintenance of improved cell patterning. The cell-seeded Gelfoam construct was found to feature a user-friendly, reproducible, and atraumatic technique. © 2009 The Society of Thoracic Surgeons.