Background: In National Wilms Tumor Study-5, tumor-specific combined loss of heterozygosity (LOH) of chromosomes 1p and 16q was associated with adverse outcome in patients with favorable histology Wilms Tumor (FHWT): stage I/II patients treated with Regimen EE4A (vincristine (VCR)/dactinomycin (DACT)) had 4-year EFS of 91.2% without LOH and 74.9% with LOH; stage III/IV patients treated with Regimen DD4A (VCR/ DACT/doxorubicin(DOX)) and radiotherapy (RT) had 4-year EFS of 83% without LOH and 65.9% with LOH. The AREN0533/AREN0532 studies assessed whether augmenting therapy would improve EFS for FHWT with combined 1p/16q LOH. Stage I/II patients were treated with the addition of DOX (Regimen DD4A) but no RT. Stage III/IV patients were treated with Regimen M (VCR/DACT/DOX alternating with cyclophosphamide/etoposide) and RT. Methods: Patients were enrolled through the AREN03B2 Biology and Classification study between10/2006 and 7/2013. All patients underwent central review of pathology, surgical reports and diagnostic imaging. Tumor tissue was evaluated for LOH 1p and 16q by microsatellite testing. Descriptive statistics were used to compare the EFS/OS between NWTS-5 and the current studies. Results: Median follow up for 1,134 patients enrolled on AREN0532/0533 was 3.6 years (0.1 to 8.1 years). Combined LOH 1p and 16q was detected in 35 evaluable stage I/II patients and 52 stage III/IV patients. At analysis in December 2014 the number of events was 6 observed versus 9 expected for stage I/II, and 4 observed versus 18 expected for stage III/IV. The 4 year EFS for the stage I/II LOH patients and stage III/IV LOH patients was 83.9% (95%CI: 64.9%, 93.1%) and 91.5% (95%CI: 78.5%, 96.8%) respectively. Grade 3 or higher hematological toxicity was the most common toxicity observed with Regimen M, affecting 60% of patients. There were no unexpected toxicities. Conclusions: Regimen M therapy improved EFS for patients with stage III/IV FHWT with LOH at 1p/16q as compared to the historical comparison group treated with Regimen DD4A. The benefit of using Regimen DD4A instead of Regimen EE4A for stage I/II FHWT with LOH is less clear. Clinical trial information: NCT00379340; NCT00352534