Objective To construct three kinds of collagen-chitosan porous scaffolds with enhanced biostability and to investigate the histocompatibility of the scaffolds in vivo. Methods Collagen-chitosan porous scaffolds were fabricated by freeze-drying method, cross-linked using dehydrothermal treatment and glutaraldehde, respectively. The morphology of the uncross-linked scaffold (scaffold1), dehydrothermally cross-linked scaffold (scaffold 2) and glutaraldehde crosslinked scaffold (scaffold 3) was studied by scanning electron microscopy. Threekinds of scaffolds were embedded subcutaneously on dorsal surface of 12 rabbit ears. The general and local responses were recorded daily. The biostability and histocompatibility of the scaffolds were observed by using HE staining after 3, 7, 14 and 28 days of operation. Results The scaffolds had three-dimensional porous structures with a porosity of more than 90%, and possessed pore sizes of 120±10 μm, 80±15 μm and 170±20 μm, respectively. All experimental rabbits survived with good general condition during the study. All skin incisions healed well without obvious reactive red or swelling. Histological study showed that scaffold 1 was degraded rapidly with obvious inflammation. The degradation of scaffold 2 was slower than that of scaffold 1 and the inflammation of scaffold 2 was also milder than that of scaffold 1. Scaffold 3 possessed slow degradation property with slight inflammatory reaction, and rapid tissue regeneration. Conclusion The collagenchitosan porous scaffolds have three-dimensional porous structures that are suitable for tissue regeneration. The biostability and histocompatiility of the scaffolds are enhanced after cross-linked. Glutaraldehde cross-linked is better than dehydrothermally cross-linked, which can facilitate dermal tissuereconstruction.