To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA). ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. The NA subgroup consisted of 497 subjects in the A+AVD ( = 250) and ABVD ( = 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint modified progression-free survival (PFS) per independent review demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60; = 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50; = 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD. The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.