We propose a large animal model for bone tissue engineering that yields quantitative data and simulates clinical methods and tissue needs. Skeletally mature domestic sheep (n = 20) were each implanted with three rectangular (1 x 1 x 4 cm), hollow tissue-molding chambers that were empty (control) or filled with equal weights (6.71-6.78 g) of particulate autologous bone graft (MBG) or bone graft that was autoclaved to denature stored growth factors (DeMBG). MBG provided scaffold and bioactive factors, and DeMBG provided only scaffold. The chambers were enclosed on five sides and securely implanted so that the open face was apposed to the osteogenic (i.e., cambium) layer of the rib periosteum for 3, 6, 9, 12, or 24 weeks, after which the chambers were harvested and the contents analyzed. Each chamber contained osseous and fibrovascular tissue. MBG-containing chambers had the best maintenance of tissue volume compared with DeMBG-containing or empty chambers, but it still decreased steadily over time. Despite this, the MBG-containing chambers showed continuous active bone formation. There was increasing calcified tissue with penetration of osteogenesis up to a mean of 0.75 +/- 0.15 cm from the periosteum by 9 weeks, and the osteogenic area peaked at 0.59 +/- 0.13 cm2 by 12 weeks. Using quantitative measures that reflect clinical needs (i.e., tissue volume, shape, and quality), it was possible to distinguish differences in performance associated with manipulation of implanted scaffold and bioactive factors. This ovine model may serve as a useful tool to develop clinical osseous tissue-engineering strategies.