Background: Most patients with localized RMS achieve complete remission during standard (std) treatment but approximately 20-30% of them relapse and chance of salvage is poor. We tested whether adding maintenance metronomic chemotherapy after std chemotherapy would improve survival for patients with non metastatic RMS defined as HR according to EpSSG stratification. Methods: Patients (pts) age >6 months <21 years, with N0 alveolar (A)RMS or incompletely resected (Group II or III) embryonal (E)RMS arising in an unfavorable primary site and/or N1 in complete remission after std treatment including 9 cycles of ifosfamide, vincristine and actinomycin D +/- doxorubicin, surgery and/or radiotherapy were eligible for randomization to stop treatment (Std-arm) or receive maintenance chemotherapy (M-arm) with 6 28-day cycles of iv vinorelbine 25 mg/m² on day 1,8,15 of each cycle and continuous daily oral cyclophosphamide 25 mg/m² . The study was initially designed with 80% power (5% 2-sided alpha level) to detect an increase in 3 yr Event Free Survival (EFS) from 55% to 67%, a Hazard Ratio of 0.67, but was successively amended to allow a detection of a relative reduction in the relapse rate of 50% in the M-arm, with 80% power, testing at the 5% significance level (2-sided). Results: 670 pts were entered between 4/2006-12/2016, with 371 confirmed eligible and 186 assigned to the std-arm and 185 to M-arm. Clinical features were well balanced in the two arms and included ERMS 67%, ARMS 33%, age 10+ years 21%; IRS Group III 86%; N1 16%. Most common primary tumor sites were parameningeal (32%) and “other” sites (23%). With median follow up of 5 years in surviving pts, 3 yr EFS and overall survival (OS) in M-arm vs Std-arm were respectively: EFS 78.4% (95% IC -71.5-83.8) vs 72.3% (95% IC -65.0-78.3) (p 0.061) and OS 87.3% (95% IC 81.2-91.6) vs 77.4 (95% IC 70.1-83.1) (p = 0.011). Toxicity in the M-arm was manageable: grade 3/4 febrile neutropenia in 25% of pts, grade 4 neurotoxicity in 1.1%. Conclusions: The addition of maintenance after std treatment significantly improves OS in HR RMS patients and support its inclusion in future EpSSG trials. Clinical trial information: 2005-000217-35.