Background: The long-term event free survival (EFS) for IRRMS is 65%. Since VI had significant activity in metastatic and recurrent RMS, we tested whether adding VI to VAC would improve EFS for IRRMS. Methods: Patients (pts) with alveolar (A)RMS or incompletely resected (Group III) embryonal (E)RMS arising in an unfavorable primary site (Stage 2/3), both without distant metastases, < 50 years, and adequate organ function were eligible to be randomized to 42 weeks of VAC (V=1.5 mg/m², A=0.045 mg/kg, C=1.2 g/m² every 3 weeks) vs VAC/VI (I=50 mg/m²/day x 5 days) intravenously; doses were adjusted for children < 3 years; radiation therapy (36-50.4 Gy) was started at week 4, with individualized local control for children < 2 years allowed. The primary study endpoint was EFS. The study was designed with 80% power (5% 1-sided alpha level) to detect an increase in 5 yr EFS from 65% to 76%, a relative risk of 0.64. Results: 481 pts were entered between 12/2006-12/2012, with 461 confirmed eligible. Clinical features included ERMS 53%, ARMS 43%; age < 1 year 6%, 1-9 years 62%, 10+ years 32%; Group III 85%; Stage 3 61%. The most common primary tumor sites were parameningeal (44%), extremity (13%), and bladder/prostate (13%). With median follow up of 2.46 years in surviving pts, EFS and overall survival (OS) with 95% confidence intervals (CI) were similar overall and by histologic subtypes (Table). Grade 3/4 febrile neutropenia, anemia, and thrombocytopenia were less common with VAC/VI, particularly after the first 15 weeks of therapy, while diarrhea was more common with VAC/VI. Conclusions: The addition of VI to VAC did not significantly improve EFS or OS compared to VAC alone for IRRMS. The lower rate of hematologic toxicity and cumulative C dose with VAC/VI (8.4 g/m² vs 16.8 g/m²) support the use of VAC/VI as the standard arm in future IRRMS trials. Clinical trial information: NCT00354835.