We studied the role of immunosuppressive therapy in improving the incorporation of frozen bone allografts exchanged across strong transplantation barriers in a canine cancellous ulnar segmental replacement model. Dogs receiving frozen bone from donors with major histocompatibility differences received one of three different immunosuppressive treatments. In two groups, azathioprine and prednisolone were administered for either twenty-eight or fifty-six days; anti-lymphocyte globulin was added for another twenty-eight-day group in a third regimen. Frozen bone was evaluated radiographically and histologically by criteria that quantified the biological characteristics of the bone itself and union between the graft and host at thirteen and twenty-six weeks after grafting. Graft incorporation in these animals was compared with graft acceptance in a similar group of untreated animals and in untreated animals in which bone was exchanged across weak transplantation barriers. Complications of immunosuppression included wound drainage, infection, weight loss, and falling white-blood-cell counts. Seven of the original thirty-seven animals died as a direct result of these complications. After twenty-six weeks the grafts in the recipients receiving immunosuppression appeared radiographically and histologically indistinguishable from those in the untreated, genetically closely matched group and from autografts. They were significantly better incorporated than identical allografts placed in untreated, genetically disparate recipients. There was no difference in the effectiveness of any of the immunosuppressive programs. Clinical Relevance: Immunosuppression improves the biological outcome of otherwise poorly performing frozen bone allografts in dogs. This finding suggests that treatments that modify the immunological response of the host without major side effects may be useful clinically in improving the success of massive frozen bone allografts.