We previously identified a hyaluronan-associated protein collagen complex (HA-PC) from 100-day gestation fetal sheep skin. SDS gel showed the dominant protein associated with hyaluronan from this complex to be a 62kDa peptide (HA-AP). Selective digestion studies showed this protein moiety to have significant in vitro wound healing properties including increased epithelialization and fibroblast proliferation. In the ensuing in-vivo study, HA-AP promoted wound closure and improved wound quality by altering the expression of TGF-b isoforms. Sequencing the HA-AP by the nitrocellulose electroblot method permitted N-terminal sequence analysis through 15 residues. Comparison with known protein sequences revealed only calreticulin shared a similar N-terminus. Calreticulin is a low-affinity, high-capacity, intraendoplasmic reticulum calcium-binding protein found in nonskeletal muscle cells of most mammalian species. Calreticulin might have a role in wound healing because it is known to bind certain alpha subunits of integrins, the cell surface proteins mediating many cell-cell and cell-matrix interactions during wound repair. Calreticulin may also effect wound healing by modulating the acute inflammatory response. We conducted this study to determine whether calreticulin represents biologically active HA-AP extracted from fetal sheep skin during the period of scarless wound healing. This data for the first time confirm the biologic importance of calreticulin as an effector of wound healing in an in vivo model.