Introduction: PET-guided treatment of newly diagnosed advanced stage (AS) classical Hodgkin Lymphoma (cHL) patients with eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procar-bazine, prednisone) achieves outstanding survival outcomes, but also causes relevant treatment-related morbidity (TRMB). CD30-targeted therapy with brentuximab vedotin (BV) has proven high efficacy and favorable tolerability in patients with cHL. In the HD21 study, we hypothesized that using BV to remodel the eBEACOPP regimen could further decrease TRMB while maintaining its high efficacy. Here, we report the final analysis of the TRMB endpoint. Methods: Adult patients ≤ 60 years of age with AS-cHL were included in this international randomized phase III trial. Patients were randomized in a 1:1 ratio to PET2-guided 4–6 cycles of either standard eBEACOPP or experimental BrECADD treatment (BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone). PET2 was assessed by blinded panel review (PP-2). Reduction of TRMB was the first part of the co-primary endpoint, whereas non-inferiority of progression-free survival (PFS) was the second part. TRMB was defined as any CTCAE grade 3 or 4 organ toxicity or grade 4 hematological toxicity (anemia, thrombocytopenia, infection) during treatment. TRMB was determined using the Cochran-Mantel-Haenszel method. Stratification factors included sex, age, IPS, and location of trial site. Categorical variables were compared using fisher’ s exact test. Exploratory analyses were performed for further safety outcome parameters. The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Results: Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries. 1,470 patients are in the intention-to-treat (ITT) population (eBEACOPP n=732, BrECADD n=738). Baseline characteristics such as sex (male=56%), age (≤45 years=79%), IPS (0–2=54%), location (Europe=92%) and stage (III/IV=84%) were well balanced between treatment arms. As recommended by PP2, 59% of patients had 4 cycles and 41% received 6 cycles of therapy, without differences between treatment groups. TRMB was documented in 59% of patients in the eBEACOPP group (rel-risk, 1.41; 95% CI, 1.27–1.56, p<0.001) and 42% in the BrECADD group (rel-risk, 0.72; 95% CI, 0.65–0.79, p<0.001). The relative risk estimates remained stable among stratification factors. In the eBEACOPP group 52% of patients had hematological TRMB events compared to 31% in the BrECADD group (p<0.001). At least one red cell transfusion was given in 22% of patients in the eBEACOPP group and in 8% in the BrECADD group and at least one platelet transfusion in 13% and 6%, respectively. Severe leukopenia was observed in 94% and 87%, respectively. TRMB organ toxicity was documented in 17% of patients in the eBEACOPP group and 19% in the BrECADD group (p=0.455). Conclusion: The BrECADD regimen shows a significant and clinically relevant reduction of treatment-related morbidities compared to eBEACOPP in patients with newly diagnosed AS-cHL.