Objective We compared the histologic findings in explanted CorMatrix (9 patients) and autologous pericardium (9 patients) used for valvuloplasty of the aortic (7 patients) and/or mitral (11 patients) valve in patients with congenital heart defects. Methods We used standard tissue stains and immunohistochemistry to identify the inflammatory cell type. Results CorMatrix was associated with an intense inflammatory response in the surrounding native tissue, extending into CorMatrix in 8 of 9 cases, continuing to the longest follow-up point (9 months). The typical response included macrophages and giant cells in contact with the material, surrounded by lymphocytes, macrophages, plasma cells, and eosinophils. The thickness of the residual CorMatrix material was 280 to 300 μm, similar to the nominal thickness at implantation and unrelated to the implantation duration. Only at the longest follow-up interval was any significant resorption of CorMatrix material evident. A neointima had formed on the surface of CorMatrix, increasing in thickness with the period in situ. Mild cellular infiltration of CorMatrix was noted in all cases; however, in no case, did it appear that CorMatrix was being remodeled into tissue resembling a 3-layered native valve. In contrast, a near absence of any inflammatory reaction was seen and no eosinophilia associated with autologous pericardium was present, irrespective of the duration in situ. Furthermore, we observed more tissue infiltration, remodeling, vascularization, and neointima formation with autologous pericardium. Conclusions Although CorMatrix used for valve repair induced an intense inflammatory response, little or no remodeling to form tissue resembling a 3-layered native valve was seen at ≤9 months after implantation.