Objective: To investigate the clinicopathological and radiological features of benign fibro-osseous lesion (BFOL). Methods: Sixty-five cases of craniofacial BFOL, eight cases of peripheral ossifying fibroma (POF) and one case of low-grade central osteosarcoma diagnosed at Sichuan Provincial People's Hospital between January 2010 and March 2019 were collected. The clinicopathologic features, hematoxylin-eosin and immunohistochemical (IHC) staining and radiographic features were analyzed. MDM2 gene amplification was detected by FISH in difficult borderline cases. Results: This cohort of BFOLs included 50 cases of fibrous dysplasia (FD), 12 cases of ossifying fibroma (OF), and three cases of juvenile psammomatoid ossifying fibroma (JPOF). The average ages of patients with FD,OF and JPOF were 31.7, 39.2 and 26.0 years respectively. The male to female ratio was 1.0∶1.8.The average age of POF was 47.0 years, with male to female ratio of 1∶7. Patient of low-grade central osteosarcoma was a 48-year-old man. Twenty-seven cases of FD were located in the jaw, and 23 cases were in other craniofacial bones. Nine cases of OF were located in the jaw, and three cases were in the nasal cavity. Two cases of JPOF were in the nasal sinus, and one was in the jaw. All POF were located in the gingiva, and low-grade central osteosarcoma was located in the mandible. The imaging features of FD were luffa-like or ground-glass like signal shadows with poorly defined borders with expansion. OF had clear borders or sclerosing margins. Both JOF and low-grade central osteosarcoma were expansile intraosseously and with focally invasive nodular masses with ground-glass like signal shadows; and POF showed soft tissue mass with bone formation. Histological features of BFOLs showed mixed fibrous and irregular osteoid lesions. FD had no clear relationship with the host bone and no osteoblasts surrounded the bone trabeculae. Osteoblasts rimming was found in OF, and the boundaries of the host bone were clear. JPOF and low-grade central osteosarcoma infiltrated the host bone focally, and the latter showed mild cellular atypia. MDM2 amplification was detected in low-grade central osteosarcoma. Conclusions: BFOLs are a group of fibro-osseous lesions with similar morphology in the head and neck and face, but their clinical features and prognosis are different; and their imaging and histological characteristics are also slightly different. Attentions should be given to the combination of clinical, imaging and pathologic features of BFOLs, especially the differential diagnosis between BFOLs and low-grade central osteosarcoma. Molecular detection could be used to assist the diagnosis in difficult cases.