Malignant transformation of fibrous dysplasia (FD) in long bones is rare (less than 1% of cases) and occurs in the form of osteosarcomas. They can occur on FD associated with multiple myxomas, which corresponds to Mazabraud syndrome. To our knowledge, only six cases of FD malignant transformation into osteosarcoma in the context of Mazabraud syndrome have been described. Here, we describe the first case of malignant transformation of femur FD into chondrosarcoma in a 51-year-old female patient. The patient had significant changes in the size and number of myxomas around the femur before the malignant transformation into chondrosarcoma. She underwent complete femur replacement with a favourable result after 4 years’ follow-up. Close surveillance is strongly recommended in this syndrome, particularly when the number and size of myxomas increase.