The biologic response to injectable, glutaraldehyde cross-linked, fibrillar collagen implants in the rat subcutaneous model was shown to be a function of the concentration of glutaraldehyde used for cross-linking. The collagen was prepared from bovine hide by pepsin solubilization and reconstituted as a fibrillar suspension of 35 mg collagen/mL. Fibrillar collagen implants cross-linked with glutaraldehyde concentrations equal to or less than 0.01% exhibited a response characterized by fibroblast invasion, neovascularization and little, if any, evidence of inflammation. Implants cross-linked with 0.1 and 1.0% glutaraldehyde elicited a foreign body/giant cell reaction and varying degrees of implant erosion. The interaction of human skin fibroblasts with 0.01% glutaraldehyde cross-linked collagen in vitro was found to be dependent on the culture conditions utilized to evaluate the interaction. When the ratio of cell culture media to collagen was 20:1, cell invasion of the cross-linked preparations was observed, whereas, when this ratio was reduced to 1:1, such interactions could not be detected. Noncross-linked preparations were colonized by cells regardless of the experimental conditions used. Studies of implants in both the rat and guinea pig subcutaneous models indicated that glutaraldehyde cross-linking concentrations as low as 0.0075% provided enhanced wet weight recovery (wet weight persistence) and resistance to biologic degradation (collagen persistence) as compared to noncross-linked fibrillar collagen preparations. These cross-linked implants also exhibited a greater degree of fibroblast infiltration and vascularization. Between 30 and 60 days, some degree of calcification developed in both collagen formulations implanted in rats and guinea pigs; however, the reaction occurred with greater frequency and intensity in cross-linked preparations in guinea pigs. Calcification in the guinea pig was followed by the appearance of focal areas of ossification.