Background: Children’s Oncology Group study AEWS0031 demonstrated superior 5-year event-free survival (EFS) in patients with localized Ewing sarcoma (ES) receiving interval-compressed (IC) chemotherapy (every 2 weeks) compared to standard timing (ST) chemotherapy (every 3 weeks). We assessed the long-term outcome of patients treated on AEWS0031 to determine whether the survival advantage of IC chemotherapy was maintained at 10 years. Methods: AEWS0031 enrolled 568 eligible patients with localized ES. Patients were stratified into four groups by age (<18 years and ≥ 18 years) and primary site (pelvic and non-pelvic), and randomized to receive 14 cycles of alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide given every 3 weeks (ST; Regimen A) vs. every 2 weeks (IC; Regimen B). For this updated report, one patient was excluded due to uncertainty of original diagnosis giving a total of 567 patients in this analysis. Data for tumor measurements and histologic response were collected retrospectively from institutional reports. EFS and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test and Gray’s test for cumulative incidence (CI). Results: The 10-year EFS for patients treated with IC chemo was 70% compared to 61% for ST chemo (p = 0.03), and the OS was 76% with IC chemo compared to 69% for ST chemo (p = 0.03). The 10-year CI of second malignant neoplasms (SMNs) for ST chemo was 4.2% [95% confidence interval: 2.4-7.5] compared to 3.2% (95% confidence interval: 1.6-6.3) for IC chemo (p = 0.5). There was a trend towards improved 10-year EFS in those receiving IC chemo both with non-pelvic (N = 477; 71% vs. 64%) and pelvic (N = 90; 67% vs. 43%) primary tumors. Similarly, the 10-year EFS was superior for patients treated with IC chemo in both the < 18 years (N = 500; 73% vs. 64%) and ≥ 18 years (N = 67; 53% vs. 37%) age groups. Among the 184 patients with available histologic response data, the 10-year EFS from the time of local control was 76% for those with < 10% viable tumor and 56% for those with ≥ 10% viable tumor (p = 0.01). Additional analysis comparing patients with any viable tumor vs. no viable tumor (NVT) by treatment regimen demonstrated that patients with NVT who received IC chemo had 10-year EFS and OS from local control of 91% and 97%, respectively. In the 210 patients for whom tumor volume calculations were possible, there was no difference in the 10-year EFS for patients with tumors < 200 mL vs. ≥ 200 mL. Conclusions: With longer term follow-up, IC chemotherapy for localized ES is associated with superior EFS and OS without an increase in SMNs. This study suggests patients ≥ 18 years with poor necrosis or pelvic primary tumors remain at high risk for relapse despite IC chemo, emphasizing the need for alternative treatment strategies to improve their outcomes. Clinical trial information: NCT00006734.