There are few synthetic graft alternatives to treat large long-bone defects resulting from trauma or disease that do not incorporate osteogenic or osteoinductive factors. The aim of this study was to test the additional benefit of including a permeable collagen membrane guide in conjunction with a preformed porous hydroxyapatite bone graft to serve as an improved osteoconductive scaffold for bone regeneration. A 10-mm-segmental long-bone defect model in the rabbit radius was used. The hydroxyapatite scaffolds alone or with a collagen wrap were compared as experimental treatment groups to an empty untreated defect as a negative control or a defect filled with autologous bone grafts as a positive control. All groups were evaluated after 4 and 8 weeks of in vivo implantation using microcomputed tomography, mechanical testing in flexure, and histomorphometry. It was observed that the use of the wrap resulted in an increased bone volume regenerated when compared to the scaffold-only group (59% greater at 4 weeks and 27% greater after 8 weeks). Additionally, the increase in density of the regenerated bone from 4 to 8 weeks in the wrap group was threefold than that in the scaffold group. The use of the collagen wrap showed significant benefits of increased interfacial bone in-growth (149% greater) and periosteal remodeling (49%) after 4 weeks compared to the scaffold-alone with the two groups being comparable after 8 weeks, by when the collagen membrane showed close-to-complete resorption. While the autograft and wrap groups showed significantly greater flexural strength than the defect group after 8 weeks, the scaffold-alone group was not significantly different from the other three groups. It is most likely that the wrap shows improvement of function by acting like a scaffold for periosteal callus ossification, maintaining the local bone-healing environment while reducing fibrous infiltration (15% less than scaffold only at 4 weeks). This study indicates that the use of a collagen membrane with a hydroxyapatite structural graft provides benefits for bone tissue regeneration in terms of early interfacial integration.