Objective: Primary concerns about currently available pericardial substitutes include adhesion and epicardial reaction. The purpose of this study is to evaluate host reaction to pericardial substitutes with and without incorporating slow heparin release. Methods: To avoid biologic variation among these pericardial patches, we made a composite of six membranes. The composite membrane consisted of epoxy-fixed patches with (1) or without (2) ionically bound heparin, a glutaraldehyde-fixed patch with (3) or without (4) ionically bound heparin, an expanded polytetrafluoroethylene patch (5), and a polyester polymeric patch (6). Ten recipient dogs weighing from 12 to 19 kg (mean 13.6 kg) were used to assess the composite membranes as pericardial substitutes. The implanted composite membranes were retrieved 1 week (one dog), 2 weeks (one dog), 4 weeks (one dog), 8 weeks (one dog), and 12 weeks (six dogs) after implantation. Results: Overall, the synthetic patches had a more notable inflammatory reaction than the biologic patches with or without ionically bound heparin. The heparin-bound patches caused significantly less inflammation than their nonheparinized counterparts. The heparinized porcine patches crosslinked with different compounds were found to have less fibrous formation than the nonheparinized patches and the synthetic patches. Conclusions: Heparinized pericardial substitutes may cause less adhesion and inflammatory reaction than nonheparinized material.