Various cell delivery methods have been investigated for cell transplantation treatment of cardiac infarcts. In this study, we investigated a type I collagen-glycosaminoglycan (GAG) scaffold for the implantation of adult bone marrow-derived mesenchymal stem cells (MSCs) into the infarcted region in the rat heart. The objective was to evaluate the tissue response to collagen-GAG scaffolds prepared using 2 cross-linking methods. The left coronary artery of female Wistar rats was occluded for 60 min, followed by reperfusion. One week later, the infarcted region was implanted with (1) collagen-GAG scaffolds cross-linked by dehydrothermal treatment alone (DHT; n = 10); (2) collagen-GAG scaffolds cross-linked by DHT followed by carbodiimide treatment (EDAC; n = 8); or (3) DHT cross-linked collagen-GAG scaffolds seeded with bromodeoxyuridine (BrdU)-labeled allogeneic MSCs (cell-scaffold; n = 9). Shamoperated rats served as controls (n = 4). Specimens were harvested 3 weeks after the implantation surgery. The tissue response was evaluated histomorphometrically and by immunohistochemistry to track the BrdU-labeled MSCs. Most of the DHT cross-linked collagen-GAG scaffolds degraded, whereas the scaffolds in the EDAC group appeared to be largely intact. There were no signs of acute inflammation in any of the groups. A substantial amount of neovascularization was seen in the infarcted region in the implant groups and in the scaffolds themselves. BrdU-positive cells appeared both in the degraded scaffold and the infarct region. DHT cross-linked collagen-GAG scaffolds warrant continued investigation as delivery vehicles for implantation of cells into infarcted cardiac tissue.