Reconstituted keratin has shown promise as an orthopaedic biomaterial. This in vivo study investigates the biological response of composite materials prepared from reconstituted keratin containing a high content of hydroxyapatite (HA) (40 wt % HA), implanted for up to 18 weeks in the long bones of sheep. Keratin-HA composites were compared with a commercially available polylactic acid (PLA) HA composite (BIO RCI HA®, Smith and Nephew). Porous keratin-HA materials displayed excellent biocompatibility and osseointegration, with full integration into bone by 12 weeks. Dense keratin-HA materials also showed excellent biocompatibility, with a more limited osseointegration, involving the penetration of new bone into the periphery of the implant after eight weeks. In contrast, the PLA-HA implant did not integrate with surrounding tissue. Microindentation showed that porous keratin-HA implants were initially soft, but became stiffer as new bone penetrated the implant from four weeks onwards. In contrast, although the initial rigidity of dense keratin-HA composites was maintained for at least two weeks, the implant material weakened after four weeks. The PLA-HA implant maintained its physical properties throughout the course of the trial. This study demonstrates the increased osseointegration/osteoconduction capacity of keratin-HA composites and provides further evidence supporting the suitability of keratin-based materials, such as bone graft substitutes and soft tissue fixation devices.