Background: Biologic scaffold materials prepared from extracellular matrix are currently available for the surgical repair of damaged or missing musculotendinous tissue. These scaffolds differ in their species and tissue of origin, methods of processing, and methods of terminal sterilization. The purpose of the present study was to evaluate the host-tissue morphologic response to five commercially available extracellular matrix-derived biologic scaffolds used for orthopaedic soft-tissue repair in a rodent model. Methods: One hundred twenty-six Sprague-Dawley rats were divided into six groups of twenty-one animals each. A defect was created in the musculotendinous tissue of the abdominal wall of each animal and then was repaired with one of five different scaffold materials (GraftJacket, Restore, CuffPatch, TissueMend, Permacol) or with the excised autologous tissue. Three animals from each group were killed at one of seven time-points after surgery (two, four, seven, fourteen, twenty-eight, fifty-six, and 112 days), and the specimens were examined with histologic and morphologic methods. The degree of cellular infiltration, multinucleated giant cell presence, vascularity, and organization of the replacement connective tissue were evaluated with semiquantitative methods. Results: Each device elicited a distinct morphologic response that differed with respect to cellularity (p < 0.001), vascularity (p < 0.01), the presence of multinucleated giant cells (p < 0.01), and organization of the remodeled tissue (p < 0.01) at or after the Day 7 time-point. More rapidly degraded devices such as Restore and autologous tissue showed the greatest amount of cellular infiltration, especially at the early time-points. Devices that degraded slowly, such as CuffPatch, TissueMend, and Permacol, were associated with the presence of foreign-body giant cells, chronic inflammation, and/or the accumulation of dense, poorly organized fibrous tissue. Conclusions: Biologic scaffold materials composed of extracellular matrix elicit distinct host-tissue histologic and morphologic responses, depending on species of origin, tissue of origin, processing methods, and/or method of terminal sterilization. Clinical Relevance: The temporal sequence of remodeling events of extracellular matrix devices, including the rapidity of scaffold degradation and the extent of new-tissue deposition by the host, may be predictive of the clinical course and may determine the optimal rehabilitation protocol and functional outcome of the procedure.