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Objective: We compared clinical characteristics and renal response in patients with childhood‐onset proliferative lupus nephritis (LN) treated with the EuroLupus versus National Institutes of Health (NIH) cyclophosphamide (CYC) regimen. Methods: A retrospective cohort study was conducted at 11 pediatric centers in North America that reported using both CYC regimens. Data were extracted from the electronic medical record at baseline and 3, 6, and 12 months after treatment initiation with CYC. To evaluate the adjusted association between CYC regimen (EuroLupus vs NIH) and renal response over time, generalized estimating equations with a logit link were used. An interaction between time and CYC regimen was included, and a contrast between CYC regimens at 12 months was used to evaluate the primary outcome. Results: One hundred forty‐five patients (58 EuroLupus, 87 NIH) were included. EuroLupus patients were on average older at the start of current CYC therapy, had longer disease duration, and more commonly had relapsed or refractory LN compared with the NIH group. After multivariable adjustment, there was no significant association between CYC regimen and achieving complete renal response at 12 months (odds ratio [OR] of response for the EuroLupus regimen, reference NIH regimen: 0.76; 95% confidence interval [CI] 0.29–1.98). There was also no significant association between CYC regimen and achieving at least a partial renal response at 12 months (OR 1.35, 95% CI 0.57–3.19). Conclusion: Our study failed to demonstrate a benefit of the NIH regimen over the EuroLupus CYC regimen in childhood‐onset proliferative LN. However, future prospective outcome studies are needed. [ABSTRACT FROM AUTHOR]