Purpose : Describe clinical characteristics and outcome of Li-Fraumeni-associated osteosarcomas. Methods : TP53 germline pathogenic/likely pathogenic variant carriers diagnosed with osteosarcoma in France between 1980 and 2019 were identified via the French Li-Fraumeni database at Rouen University Hospital. Sixty-five osteosarcomas in 52 patients with available clinical and histological data were included. The main clinical characteristics were compared with data from the SEER (National Cancer Institute’s Surveillance, Epidemiology, and End Results) for patients of the same age group. Results : Median age at first osteosarcoma diagnosis was 13.7 years (range:5.9-36.7). Compared to unselected osteosarcomas, LFS-associated osteosarcomas occurred more frequently in patients <10 years (23% versus 9%) and, when compared with osteosarcomas in patients <25 years were characterized by an excess of axial (16% versus 10%) and jaw sites (15% versus 3%) and histology with predominant chondroblastic component (35% versus 16%) and periosteal subtypes (17% versus 1%). Metastases incidence (25%) was as expected in unselected osteosarcomas. After the first osteosarcoma treatment, the rate of good histologic response (62%) and the 5-year progression-free survival (55%[95%CI:42.6−71.1]) were as expected in unselected series of osteosarcomas whereas the 5-year event-free survival was 36.5%[95%CI: 25.3−52.7] due to the high incidence of second malignancies reaching a 10-year cumulative risk of 55.3%[95%CI:34.3-69.5]. Conclusion : In osteosarcoma, young age at diagnosis, axial and jaw sites, histology with periosteal or chondroblastic subtype and synchronous multifocal tumors should prompt suspicion of a germline TP53 mutation. Standard treatments are effective, but multiple malignancies impair prognosis. Early recognition of these patients is crucial for tailored therapy and follow-up.