Ezrin is a cytoskeleton linker protein that is actively involved in the metastatic process of cancer cells. We have recently reported that ezrin expression in conventional osteosarcoma was an independent prognostic factor for event-free survival and overall survival. In this work, ezrin expression was found in all histological subtypes. Especially cartilaginous areas in chondroblastic osteosarcomas were immunopositive for ezrin. We wanted to know if ezrin could be a useful diagnostic marker in bone pathology. We have searched for ezrin expression in 208 cartilaginous tumours by immunohistochemistry and in 16 chondroblastic osteosarcomas. All conventional chondrosarcomas, whatever their grade, were negative, while ten of 16 chondroblastic osteosarcomas were positive. In contrast, dedifferentiated (five of 14) and mesenchymal chondrosarcomas (five of ten) showed ezrin positivity. Some chondroblastomas and more rarely chondromyxoid fibromas also exhibited ezrin expression. These data suggest that ezrin is a useful immunohistochemical marker for differential diagnosis between chondroblastic osteosarcomas and conventional chondrosarcomas with a specificity of 100%. Ezrin expression in dedifferentiated and mesenchymal chondrosarcomas which are aggressive neoplasms resistant to conventional treatment means that ezrin could be a therapeutic target. Ezrin expression in chondroblastomas is more intriguing and requires further study to assess prognostic value.