The present study analyzed the tissue reaction to 2 novel porcine-derived collagen materials: pericardium versus dermis. By means of the subcutaneous implantation model in mice, the tissue reactions were investigated at 5 time points: 3, 10, 15, 30, and 60 days after implantation. Histologic, histochemical, immunhistologic, and histomorphometric analysis methodologies were applied. The dermisderived material underwent an early degradation while inducing mononuclear cells together with some multinucleated giant cells and mild vascularization. The pericardium-derived membrane induced 2 different cellular tissue reactions. The compact surface induced mononuclear cells and multinucleated giant cells, and underwent a complete degradation until day 30. The spongy surface of the membrane induced mainly mononuclear cells, and served as a stable barrier membrane for up to 60 days. No transmembranous vascularization was observed within the spongy material surface layer. The present data demonstrate the diversity of the cellular tissue reaction toward collagen-based materials from different tissues. Furthermore, it became obvious that the presence of multinucleated giant cells was associated with the material breakdown/degradation and vascularization. Further clinical data are necessary to assess extent to which the presence of multinucleated giant cells observed here will influence the materials stability, integration, and, correspondingly, tissue regeneration within human tissue.