Background: A ISG randomized trial on 5 cycles of adjuvant epirubicin+ifosfamide (EI) versus no chemotherapy suggested an OS benefit in localized high-risk STS (JCO 2001;19:1238). A subsequent trial showed no difference between 3 vs 5 cycles of the same neoadjuvant regimen (JCO 2012;30:850). The aim of this trial was to compare 3 cycles of EI versus a histology-tailored (HT) neoadjuvant regimen in selected localized high-risk STS. Methods: This is a multicenter European randomized trial comparing EI versus a HT regimen: gemcitabine+docetaxel in undifferentiated pleomorphic sarcoma (UPS); trabectedin in high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma (SS); etoposide+ifosfamide in malignant peripheral nerve sheath tumors (MPNST); gemcitabine+dacarbazine in leiomyosarcoma (LMS). Patients had localized high-risk (grade = 3; size ≥5 cm) STS of extremities or trunk wall. Primary end-point was Disease Free Survival (DFS). The final analysis was planned after the observation of 130 events. This allows an 80% power to detect a significant difference at the 5% 2-sided level, if the true HR is 0.6 in favor of EI, as shown by the interim analysis (Lancet Oncol 2017;18:812-822). Results: From May 2011 to May 2016, 287 patients were randomized (97 = UPS; 65 = myxoid liposarcoma; 70 = SS; 27 = MPNST; 28 = LMS). The median follow-up was 51.75 months for the alive patients (IQ 28.03) The DFS and OS probability at 60 months were 0.48 and 0.55 (HR:1.232; 95%CI: 0.875-1.733; log rank p=0.323) and 0.66 and 0.76 (HR:1.766; 95%CI:1.101-2.831; log rank p=0.018), in the HT and EI arm, respectively. Conclusions: The final analysis shows a non-statistically significant DFS difference in favor of EI over HT chemotherapy with a larger and statistically significant OS difference. The outcome of patients on EI overlapped previous ISG trials. EI should remain the regimen of choice when neoadjuvant chemotherapy is used in high-risk localized STS. However this trial cannot be used as a formal proof of efficacy of (neo)adjuvant chemotherapy per se. EUDRACT 2010 – 023484 – 17. Funding source: Eurosarc FP7 278472. Clinical trial information: NCT01710176