COLLOSS E, an equine extracellular matrix product containing native transforming growth factor beta1 and several bone morphogenetic proteins, has shown osteoinductive properties in ectopic sites. This study was set up to examine its properties in an orthotoptic site in conjunction with a beta-tricalciumphosphate (beta-TCP) scaffolding material. Thirty-two 17-mm circular defects in goat mandibles were filled with COLLOSS E, beta-TCP, COLLOSS E + beta-TCP, or left empty. After 9 weeks the results were quantified by micro-computed tomography and histology. The empty defects contained the highest percentage of new bone (62%). The beta-TCP scaffold resulted in 38% (p = 0.0029), the mixture of beta-TCP/COLLOSS E resulted in 36% (p = 0.0057), while the use of COLLOSS E alone resulted in 55% (not significant p = 0.34). These results show that addition of TCP did not result in the expected synergy with regard to the healing of the defect and seemed even to inhibit the healing process. On the other hand, the addition of COLLOSS E induced the formation of small islands of new bone, not connected to the defect edges. This was not observed in the specimens not containing COLLOSS E (4.61% of bone formation centrally in the defect vs. 0.56%; p = 0.042). In conclusion, the results of the present study are somewhat unexpected in that the empty defects showed the most bone ingrowth; however, this ingrowth was always connected to the defect edges. In contrast, the application of COLLOSS E with or without beta-TCP induced bone formation in the center of the defects also.