Background: Outcomes for patients with metastatic RMS remain poor. Dose escalation of radiation may reduce risk of local failure, and maintenance therapy has prolonged survival in intermediate risk patients. We investigated a multimodal chemotherapeutic regimen with risk adapted local therapy and the addition of maintenance therapy following intensive chemotherapy to improve the outcome for patients with high-risk RMS. Methods: We conducted a phase 2 multi-center trial for patients with newly diagnosed high-risk (stage 4) RMS. Patients received 54 weeks of chemotherapy (vincristine/irinotecan, interval compressed vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide) followed by 4 cycles of anti-angiogenic maintenance therapy (bevacizumab, sorafenib, cyclophosphamide). Primary tumor local control consisted of surgery and photon/proton radiation therapy (RT) dependent on the degree of resection (negative margin – no RT, positive margin – 36 GyRBE, unresected ≤5cm – 50.4 GyRBE, unresected > 5cm – 59.4 GyRBE). RT was administered at Week 4 or 20 based on size/location, and to radiographically visible (non-CR) sites of metastatic disease at end of treatment. Results: Thirty-nine eligible patients with high-risk RMS (64% FOXO1 fusion positive, 74% with nodal disease, 67% Oberlin score > 1) were enrolled. Two of 13 patients with Oberlin score ≤ 1 were FOXO1 fusion positive whereas 23 of 26 patients with Oberlin score > 1 were fusion positive. Seventeen patients received maintenance therapy as planned (progression, n = 12; received alternate maintenance regimen, n = 4; other, n = 6) with a median of 4 cycles (range 1-4). Common toxicities of maintenance included palmar-plantar erythrodysesthesia (n = 9), rash (n = 7), and cystitis (n = 6). At a median follow-up of 43.5 months for survivors, 3-year EFS was 29.5% (95% CI 15.4-45.1%). Fusion positive status significantly predicted EFS (negative, 60.6% vs. positive, 9.6%, p = 0.019), whereas low Oberlin score approached significance for EFS (≤1, 56.6% vs. > 1, 16.4%, p = 0.064). The cumulative incidence of local failure was 17.5% (95% CI 6.9-32.2%). Twenty-one patients achieved CR of all metastatic sites and did not receive metastatic site RT. Of those, 7 experienced disease recurrence in a pre-existing metastatic soft tissue site. Among 4 patients who received metastatic site RT at the end of treatment, one patient experienced disease recurrence in a pre-existing metastatic site. Conclusions: The addition of maintenance therapy to intensive chemotherapy and risk adapted radiotherapy did not improve EFS in this population. Consolidative radiation should be considered for soft tissue metastatic sites regardless of radiographic response. Clinical trial information: NCT01871766.