Autogenous bone graft (autograft) remains the gold standard in the treatment of many orthopedic problems. However, graft harvest can lead to perioperative morbidity and increased cost. We tested the hypothesis that an osteoconductive matrix, beta-tricalcium phosphate (β-TCP), would be a safe and effective alternative to autograft alone. Beta-tricalcium phosphate (β-TCP) is considered as one of the most promising biomaterials for bone reconstruction. This study analyzes the outcomes of patients who received β-TCP as bone substitutes in orthopedic surgery.A total of 50 patients were enrolled in a controlled, non-inferiority clinical trial to compare the safety and efficacy of β-TCP (25 patients) with those of autograft (25 patients) in indications requiring usually autograft. These 50 patients were categorized according to the etiology and morphology of the 54 bone defects resulting from elective surgical procedures, such as 34 open-wedge high tibial osteotomies, and 20 osteonecrosis treatments with core decompression. Radiographic (healing process with or without integration of β-TCP), clinical (no other surgical procedure), functional outcomes and safety (with or without complications) were assessed through fifty-two weeks postoperatively.With regard to the primary endpoint (radiographic evolution), the fusion rate of the 34 open-wedge osteotomies was 100% (17 among 17) for patients in the group with β-TCP compared with 94% (16 among 17) for patients in the autograft group. For the 20 cavitary defects (osteonecrosis), the radiographic union rates, as determined by the presence of osseous bridging, were 100% for patients in the group with β-TCP and 100% for those in the autograft group. Clinically at one year, all quality-of-life and functional outcome data supported non-inferiority of β-TCP compared with autograft, and patients in the β-TCP group were found to have less pain and an improved safety profile.Treatment with β-TCP resulted in comparable fusion rates, less pain and fewer side effects as compared with treatment with autograft. This study established clinical parameters where the β-TCP alone can successfully support the osteogenic process.