Fibrous dysplasia (FD) and cemento-ossifying fibroma (COF) are benign fibrous-osseous lesions of the maxillofacial bones that exhibit numerous similarities in their clinicopathological aspects. However, due to differences in their clinical evolution and treatment, it is essential to diagnose these diseases with accuracy. The differences in the pathogeneses of FD and COF are largely unknown and currently there is no biomarker available for their differential diagnosis. Nonetheless, there are few studies comparing these lesions and predominantly comprised of immunohistochemical investigations of traditional bone biomarkers. Therefore, the present study aimed to quantitatively compare the proteomic and phosphoproteomic profiles of cemento-ossifying fibroma and fibrous dysplasia to shed light onto the mechanisms involved in their molecular pathogenesis and identify potential differential diagnosis biomarkers.