Background: The treatment of large osteochondral lesions of the talus (OLTs) is challenging due to the poor intrinsic reparative capability of the damaged articular cartilage. Autologous transfer of bone and periosteum has been used successfully in the treatment of large defects in animals, and therefore it was believed that this technique might show similar results in humans. The purpose of this study was to assess the outcome of an innovative technique for autologous transplantation of cancellous tibial graft with periosteal transfer in large OLTs. Methods: Forty-one patients (22 females, 19 males), with a mean age of 34.9 years (range, 18-72 years), with a large OLT (>200 mm2) were treated with autologous bone graft and periosteum transfer. OLTs averaging 310 mm2 were identified on a preoperative computed tomography scan. The procedure consisted of malleolar osteotomy, curettage of sclerotic bone, autologous bone graft from the proximal tibia, and transfixion of periosteum over the graft. Outcome measures, including the pain visual analog scale (VAS), ankle range of motion (ROM), American Orthopaedic Foot & Ankle Society (AOFAS) score, and Foot & Ankle Disability Index (FADI), were compared between preoperative and 1 and 2 years following surgery. Results: There were significant improvements in VAS pain score from 7.7 before surgery to 1.1 at 1 year after surgery and 0.4 at 2 years or more after surgery. The AOFAS and FADI scores were also significantly improved from 40.3 and 53.3 preoperatively to 95 and 93.2 postoperatively at 1 year and 95 and 93.2 at 2 or more years postoperatively, respectively. Postoperative complications included 2 patients who required removal of medial malleolar osteotomy tension bands due to symptomatic hardware. There were no nonunions or malunions of the osteotomies and no donor site complications. Conclusion: Autologous bone graft and periosteum transfer was an effective treatment for large OLTs leading to significant decreases in pain and improvement in functional scores at more than 2 years after surgery. Level of Evidence: Level IV, retrospective case series.