A nano-grade hydroxyapatite/collagen composite was prepared by an in situ synthesis technique from calcium nitrate, diammoniun hydrogen phosphate, and a cowhide collagen sol at low temperature. XRD and TEM analyses of the composite indicated that crystals formed in the collagen fibril matrix were nanohydroxyapatite with low crystallinity. Biocompatibility of the composite was evaluated by in vitro cytotoxicity test and in vivo genotoxicity and sensitization test. No mutagenic activity of the composite was observed in mouse micronucleus tests. No evidence of dermal sensitization of the composite was found in guinea pig maximization tests. The results from a filter diffusion test indicated that the composite did not induce a cytotoxic behavior. All these results suggest that the composite has excellent biocompatibility.