Background: Long term survival in HRNB patients remains a challenge with relapse as the primary cause of mortality. DFMO has been evaluated as a chemopreventative therapy in a single arm study designed to compare EFS outcomes with published rates for the Phase 3 Children’s Oncology Group ch14.18 immunotherapy trial, ANBL0032. In order to address the limitations associated with comparison to a historical control group, we used ANBL0032 patient-level data and propensity-score matching (PSM) to simulate a randomized study comparing EFS of patients treated with DFMO after ch14.18 (treated) to ANBL0032 patients who did not subsequently receive DFMO (control). Methods: A phase 2 trial enrolled a total of 140 HRNB patients in remission at the completion of disease treatment from 2012 to 2016. Patients received 2 years of continuous treatment with DFMO 750 ±250 mg/m² BID and were followed for up to 7 years. ANBL0032 enrolled a total of 1328 HRNB patients from 2001 to 2015 who were assigned to treatment with ch14.18 immunotherapy and followed for up to 10 years. With FDA input, we defined selection rules to identify like groups of treated and control patients eligible for matching, covariates of potential prognostic importance, and matching algorithm details. PSM was used to balance cohorts on their baseline demographic and characteristics, matching each treated patient with the 3 most closely scored control patients with an exact match on MYCN. The Kaplan-Meier method and Cox regression analyses were used to compare EFS (primary) and overall survival (OS) (key secondary) endpoints. Multiple sensitivity analyses were performed to further investigate the primary comparison. Results: A total of 92 treated patients and 852 control patients met selection criteria, with 91 and 516, respectively, having complete covariate data required for the analysis. Eighty-seven (94.6%) of the treated group had verified participation in ANBL0032 immediately prior to enrollment in the DFMO trial. EFS from end of immunotherapy was significantly improved in the matched DFMO group (n=90) vs. control group (n=270), with a hazard ratio of 0.48 (95% CI: 0.27, 0.85) and a p-value of 0.0114. Four-year EFS was 84.4% (95% CI 75.2, 90.5) in the DFMO group versus 72.8% (95% CI 67.0, 77.7) in the control group. OS rates were also higher for DFMO group in the matched population, with a hazard ratio of 0.36 (95% CI: 0.16, 0.79) and a p-value of 0.0105. EFS sensitivity analyses demonstrated consistent results, including those challenging selection criteria for the control population. Conclusions: Patients in remission after standard upfront therapy treated with DFMO had approximately half the risk of relapse compared to matched control patients. The PSM comparisons represent the most statistically robust findings to date supporting the benefit of DFMO as a maintenance treatment for HRNB. Clinical trial information: NCT02395666, NCT00026312.