Bone morphogenetic proteins (BMPs) are potent osteogenic proteins that induce new bone formation in vivo. However, their effect on bone healing in the trabecular bone surfaces remains challenging. We evaluated the safety and efficacy of recombinant human BMP6 (rhBMP6) applied within an autologous blood coagulum (ABC) in a surgically created wedge defect of the proximal tibia in patients undergoing high tibial osteotomy (HTO) for varus deformity and medial osteoarthritis of the knee. We enrolled 20 HTO patients in a randomized, placebo‐controlled, double‐blinded phase I/II clinical trial. RhBMP6/ABC (1.0 mg/10 mL ABC prepared from peripheral blood) or placebo (10 mL ABC containing excipients) was administered into the tibial wedge defects. Patients were followed for 0 to 24 months by clinical examination (safety) and computed tomography (CT) and serial radiographic analyses (efficacy). The results show that there were no detectable anti‐rhBMP6 antibodies in the blood of any of the 20 patients at 14 weeks after implantation. During the 24 months of follow‐up, there were no serious adverse reactions recorded. The CT scans from defects of patients treated with rhBMP6/ABC showed an accelerated bone healing compared with placebo at 9 weeks (47.8 ± 24.1 versus 22.2 ± 12.3 mg/cm³;​ p = 0.008) and at 14 weeks (89.7 ± 29.1 versus 53.6 ± 21.9 mg/cm³;​ p = 0.006) follow‐up. Radiographic analyses at weeks 6 and 24 and months 12 and 24 suggested the advanced bone formation and remodeling in rhBMP6/ABC‐treated patients. In conclusion, we show that rhBMP6/ABC at a dose of 100 μg/mL accelerated bone healing in patients undergoing HTO without serious adverse events and with a good tolerability compared with placebo alone. Overall, for the first time, a BMP‐based osteogenic implant was examined against a placebo for bone healing efficacy in the trabecular bone surface, using an objective bone mineral density measurement system.