OBJECTIVES: Major discordant diagnoses may have strong impact on therapeutic management.  So, identification of major discordant diagnoses and predictive factors were conducted in sarcoma patients. METHODS: A multicenter analysis was performed retrospectively from the prospective cohort of sarcoma patients. Inclusion criteria were patients with a diagnosis of sarcoma in 2010 and with a second opinion performed within the network RRePS (Réseau de Référence en Pathologie des Sarcomes supported be the French NCI). Major discordant diagnoses were defined as: sarcoma vs benign lesion, sarcoma vs malignant non sarcoma tumor, gastrointestinal stromal tumors (GIST) vs non GIST, and desmoid tumor vs non desmoid tumor. Patient and disease characteristics were described. Logistic regressions were used in order to define predictive factors of major discordance.  RESULTS: 3621 patients were included in the study. 438 patients (12%) had a major discordant diagnoses: sarcoma versus benign lesion (or conversely) in 155 patients (58%); sarcoma instead of malignant non sarcoma tumor (or conversely) in 103 patients (24%); gastrointestinal stromal tumors (GIST) instead of non GIST in 48 patients (11%); desmoid tumor instead of non desmoid tumor in 28 patients (6%) and other (4%). Major diagnostic discordances risks were higher (i) for malignant non sarcoma tumors compared to GIST, liposarcoma, and other sarcoma histological subtypes (p=0.004); (ii) for patients who had a previous cancer (p=0.03); (iii) for limb localization compared to trunk (p=0.004); (iv) when the second opinion was requested by the initial pathologist (p<0.01). CONCLUSIONS: This study reported that sarcoma instead of benign lesion (or conversely) is the major discordant diagnosis in sarcoma patients implying that: (i) patients who should not be treated received anticancer therapy; (ii) treatments are potentially delayed for patients who should be rapidly treated. Economics evaluations are in progress in order to advise healthcare administrators regarding systematic second reviews in the management of sarcoma.