Background: Programmed death 1 blockade via pembrolizumab monotherapy has demonstrated favourable anti-tumor activity and toxicity in patients with relapsed/refractory classical Hodgkin lymphoma (cHL). KEYNOTE-204 (NCT02684292) was a randomised, international, open-label, phase 3 study of pembrolizumab versus brentuximab vedotin for relapsed/refractory cHL. Here, we present the interim efficacy and safety analyses. Methods: Patients aged ≥18 years ineligible for autologous stem cell transplant (ASCT) or who had relapsed post-ASCT with measurable disease and Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Brentuximab vedotin-naive and -exposed patients were eligible. Patients were randomised 1:1 to pembrolizumab 200 mg IV every 3 weeks (q3w) or brentuximab vedotin 1.8 mg/kg IV q3w. The primary endpoint, assessed in the intent-to-treat population, was progression-free survival (PFS) by blinded independent central review per International Working Group 2007 criteria including clinical and imaging data after autologous or allogeneic stem cell transplant. Findings: One hundred fifty-one patients were randomised to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to the data cutoff of 25·7 (IQR 9·6) months, median PFS was 13·2 months for pembrolizumab versus 8·3 months for brentuximab vedotin (HR for disease progression or survival: 0·65 [95% CI 0·48-0·88; p=0·00271]). Grade 3-5 treatment-related adverse events (TRAEs) were experienced by 19·6% of patients with pembrolizumab and 25·0% with brentuximab vedotin; serious TRAEs occurred in 16·2% and 10·5% of patients, respectively. One treatment-related death due to pneumonia occurred in the pembrolizumab arm. Interpretation: Pembrolizumab was superior to brentuximab vedotin and demonstrated statistically significant and clinically meaningful improvement in PFS, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed/refractory cHL who have relapsed post-ASCT or are ineligible for ASCT. Trial Registration: This study is registered with ClinicalTrials.gov (NCT02684292). Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA) Declaration of Interests: John Kuruvilla: Honoraria: AbbVie, Bristol-Myers Squibb, Amgen, AstraZeneca, Celgene, Gilead Sciences, Janssen, Karyopharm Therapeutics, Merck, Novartis, Roche, Seattle Genetics; Consultancy/Advisory: AbbVie, Bristol-Myers Squibb, Gilead Sciences, Karyopharm Therapeutics, Merck, Roche/Genentech, Seattle Genetics; Research funding: Janssen, Roche Radhakrishnan Ramchandren: Consultancy/Advisory: Seattle Genetics, Sandoz-Novartis, Pharmacyclics/Janssen, Bristol-Myers Squibb; Research funding: Merck, Seattle Genetics, Janssen, Genentech Armando Santoro: Consultancy/Advisory: Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule; Speaker Bureau: Takeda, Roche, AbbVie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, Merck Ewa Paszkiewicz-Kozik: Travel, Accommodations, Expenses: Roche, Takeda, Celgene Robin Gasiorowski: Honoraria: Merck, Takeda, Novartis, AbbVie Nathalie A. Johnson: Honoraria: Roche/Genentech, Merck; Consultancy/Advisory: Roche/Genentech, Merck, Bristol-Myers Squibb, AbbVie; Research funding: AbbVie Laura Maria Fogliatto: No conflicts to disclose Iara Goncalves: Consultancy/Advisory: Janssen; Speaker Bureau: Janssen; Research funding: Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, Glaxo, Bristol-Myers Squibb Jose S. R. de Oliveira: No conflicts to disclose Valeria Buccheri: Consultancy/Advisory: AstraZeneca; Travel, Accommodations, Expenses: AbbVie, Takeda: Research funding: Merck, Roche, Seattle Genetics, Takeda Guilherme Fleury Perini: Honoraria: Janssen, Takeda; Speaker Bureau: AbbVie, Janssen Neta Goldschmidt: No conflicts to disclose Iryna Kriachok: Consultancy/Advisory: Takeda, Janssen; Expert Testimony: Takeda, Janssen; Travel, Accommodations Expenses: Takeda, Merck, AbbVie, Roche; Research funding: Janssen, Bayer, Karyopharm, Merck, Acerta, AbbVie, Debiopharm Michael Dickinson: Honoraria: Merck, Roche, Takeda, Celgene, Novartis; Consultancy/Advisory: Merck, Roche, Takeda, Celgene, Novartis; Speaker Bureau: Merck, Roche, Takeda, Celgene, Novartis; Research funding: Merck, Roche, Takeda, Celgene, Novartis; Mieczyslaw Komarnicki: No conflicts to disclose Andrew McDonald: No conflicts to disclose Muhit Ozcan: Research funding: Merck, Bayer, Roche, Janssen, Celgene, Takeda, Archigen, Novartis, AbbVie; Honoraria: Roche, Takeda, AbbVie, Amgen, Bristol-Myers Squibb Naohiro Sekiguchi: Research funding (institution): Ono, A2 Healthcare, Astellas, Janssen, Merck Sharp & Dohme, Otsuka, Pfizer, PPD-SNBL, Sumitomo Dainippon, Daiichi Sankyo, BristolMyers Squibb Ying Zhu: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Akash Nahar: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Patricia Marinello: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA; and has received travel expenses from Merck & Co., Inc. Pier Luigi Zinzani: Speakers’ bureaus for Verastem, Celltrion, Gilead, Janssen-Cilag, BristolMyers Squibb, Servier, Sandoz, Merck, Immune Design, Celgene, Portola, Roche, EUSA Pharma, Kyowa Kirin, and Sanofi; Advisory boards: Verastem, Celltrion, Gilead, Janssen-Cilag, Bristol-Myers Squibb, Servier, Merck & Co., Inc., Immune Design, Celgene, Portola, Roche, EUSA Pharma, Kyowa Kirin, and Sanofi; Consultant: Verastem, Merck, EUSA Pharma, and Sanofi. Ethics Approval Statement: The study was approved by the independent institutional review boards for each study site and conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki.