Replacement of injured myocardium by cell-based degradable scaffolds is a novel approach to regenerate myocardium. Understanding the foreign body reaction (FBR) induced by the scaffold is requisite to predict unwanted site effects or implant failure. We evaluated the FBR against a biodegradable scaffold applied on injured myocardium in mice. Cryolesions and collagen type I scaffolds (Col-I) were applied to the left ventricle of mice. Cell infiltration, neovascularization, collagen deposition, matrix metalloproteinase (MMP-8) expression, enzymatic activity and scaffold degradation were determined at different time points (2-70 days). Infiltration of mainly macrophages, neutrophils and blood vessels was completed within 14 days. High numbers of neutrophils accumulated around the Col-I fibers and degradation of Col-I fibers into small fragments was observed on day 14. Active MMP-8 co-localized with the neutrophils on day 14, indicating enzymatic degradation of Col-I by neutrophil collagenase. Highly vascularized extracellular matrix remained at day 70. No differences were observed in the FBR to Col-I after application on healthy or injured myocardium. The FBR had no adverse effects on the adjacent myocardial tissue. In conclusion, cardiac scaffolds are degraded by MMP-8 and replaced by vascularized extracellular matrix during the FBR on injured myocardium.