Background: EE99R2Loc (ISRCTN61438620) was conducted in 12 countries, by 4 cooperative groups: GPOH, SFCE/GSF, UK-CCLG, and EORTC. It evaluated effects on event-free (EFS, main endpoint) and overall survival (OS) of BuMel compared to standard chemotherapy in ES presenting with localized disease and either a poor histologic response to induction chemotherapy or large tumor volume ( > 200ml) unresected or initially resected. Methods: Eligible pts were aged < 50, received 6 VIDE courses (vincristine, ifosfamide, doxorubicin, etoposide) and 1 VAI (vincristine, actinomycin-D, ifosfamide) before randomization to BuMel with stem cell rescue or VAI x 7 courses. The estimate of hazard ratio (HR) and the p-value were corrected for the 4 previous interim analyses by the Inverse Normal Method. Results: Between 2000 and 2013, from 477 pts classified as high-risk pts, 216 pts (median age, 17 yrs) were randomized to VAI (107) or BuMel (109). Some pts requiring radiation therapy (RT) to the primary site were excluded to avoid excess organ toxicity from interaction between RT and Busulfan. 80% entered the trial because of poor histologic response after chemotherapy alone. Median follow up is 8.0 yrs, with only 3 pts lost to follow up before 3 yrs. Overall, 3yr EFS is 60.0% and OS, 73.9%. In an intention to treat analysis, the risk of an event was significantly decreased by BuMel compared to VAI: HR = 0.63 (95%CI, 0.42-0.94) p = .023 ; 3yr-EFS of 66.9% (57.6-75.0) vs. 53.1% (43.6-62.3). OS also favored BuMel, 77.8 vs. 69.9%, HR = 0.60 (0.39-0.92) p = .019. Results were consistent across subgroups, and in sensitivity analyses. Two pts died of BuMel-related toxicity and 1 after standard chemotherapy. Significantly more BuMel pts experienced severe acute toxicities, but these arose from a single high-dose course vs. multiple VAI courses. Conclusions: BuMel conferred improvement in EFS and OS with acceptable toxicity for pts with localized ES and poor histological response to chemotherapy or large tumor volume unresected or initially resected. It should be considered as a standard of care for this group of pts with localized high-risk ES and no contra-indication to BuMel. Clinical trial information: 61438620.