Approximately 30% of pediatric patients with ALCL relapse. While brentuximab vendotin has demonstrated excellent activity in ALCL, it has not been used for newly diagnosed patients. Children's Oncology Group trial ANHL12P1 determined the toxicity and efficacy of brentuximab vedotin with chemotherapy in children with newly diagnosed, non-localized, ALK+/CD30+ ALCL. From 2013 to 2017, 68 children with ALK+ ALCL were enrolled and received brentuximab vedotin (Arm BV). All patients received five-day prophase followed by six cycles of chemotherapy at 21-day intervals. Brentuximab vedotin was given on day 1 of each of the six cycles. Of the 67 eligible patients for toxicity evaluation, 66 completed all six cycles of chemotherapy resulting in 399 cycles evaluable. There were no toxic deaths, no cases of progressive multifocal leukoencephalopathy syndrome, and no cases of grade 3 or 4 neuropathy. The two-year EFS is 79.1% (95% CI, 67.2% to 87.1%). The two-year OS is 97.0% (95% CI, 88.1% to 99.2%). Fourteen patients relapsed and were the only events contributing to EFS. 11 of 14 (79%) relapses occurred within ten months of initial diagnosis, with only one patient (1.5%) having relapsed during therapy. Quantitative RT-PCR for NPM-ALK at baseline (minimal disseminated disease) demonstrated prognostic value and impacted 2-year EFS (P=0.0004). Overall, the addition of brentuximab vedotin to standard chemotherapy does not add significant toxicity, nor does it alter the desired interval between cycles. The addition of brentuximab vedotin prevented relapses during therapy and the overall and event-free survival estimates compare favorably with results obtained using conventional chemotherapy.