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Background: Approximately half of patients with localised, high-risk soft tissue sarcoma of the extremity develop metastases. We aimed to assess whether the addition of pembrolizumab to preoperative radiotherapy and surgery would improve disease-free survival., Methods: We completed an open-label, randomised clinical trial in patients with grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or dedifferentiated or pleomorphic liposarcoma of the extremity and limb girdle. Patients were enrolled at 20 academic institutions in Australia, Canada, Italy, and the USA. Patients were randomly assigned to preoperative radiotherapy then surgery (control group) or preoperative pembrolizumab with radiotherapy (initiated 1-14 days after the first dose of pembrolizumab) then surgery and postoperative pembrolizumab (experimental group). Pembrolizumab (200 mg intravenously every 3 weeks) was administered as three neoadjuvant cycles (before, during, and after radiotherapy) and 14 or less adjuvant cycles. Primary endpoint was disease-free survival. This study is registered with ClincialTrials.gov (NCT03092323)., Findings: Between Nov 18, 2017, and Nov 14, 2023, 143 participants were randomly assigned to treatment. A modified intention-to-treat analysis of 127 patients with median follow-up of 43 months showed that the experimental group (n=64) had significantly longer disease-free survival than the control group (n=63; log-rank one-sided p=0·035; hazard ratio [HR] 0·61; 90% CI 0·39-0·96). The 2-year disease-free survival increased by 15% with addition of pembrolizumab: 52% (90% CI 42-64) and 67% (90% CI 58-78) for the control and experimental groups, respectively. Disease-free survival was similarly improved with pembrolizumab for the intention-to-treat patient population (HR 0·61 [90% CI 0·39-0·95]). Grade 3 or higher adverse events occurred more frequently in the experimental group (56%) than the control group (31%)., Interpretation: Addition of pembrolizumab to preoperative radiotherapy and surgery improves disease-free survival for patients with stage III undifferentiated pleomorphic sarcoma and pleomorphic or dedifferentiated liposarcoma of the extremity, which establishes a promising new treatment option for these patients., Funding: Stand Up to Cancer and Merck Sharp & Dohme., Competing Interests: Declaration of interests YMM reports leadership roles in ASTRO and NRG Oncology and an honorarium from the University of Wisconsin–Madison. YMM, KVB, KJW, and DGK report grant funding from Stand Up to Cancer (Merck Catalyst Program) to the institution to support this study. KVB reports funding from SARC and the National Cancer Institute. AMH reports grant funding paid to Australia and New Zealand Sarcoma Association from the GPA Andrew Ursini Charitable Fund to support sample shipment to the USA and grant funding paid from Cancer Australia to Australia and New Zealand Sarcoma Association for clinical research team support for this study in Australia. YMM, AMH, SMS, and CFM report royalties from UpToDate for authorship contributions. AMH reports payment for participating on an advisory board for Teli. SMS reports grant funding from TRACON, Adaptimmune, and GlaxoSmithKline (GSK) to the institution; travel support from the National Comprehensive Cancer Network; and payment for participation in an advisory board for BioAtla. AJW reports a leadership role on the Board of Directors for SARC. VM reports grant funding from Rising Tide Foundation for Cancer Research; honoraria for presentations from Association of Northern California Oncologists and Gundersen Health System; participation in an advisory board for Forma Therapeutics; and funding to the institution from Amgen, Prelude Therapeutics, Jazz Pharmaceuticals, Astex Pharma, Oblato Therapeutics, Orbus Therapeutics, and Novartis. SA reports grant funding to the institution from SARC, Merck, TRACON, Bayer, Novartis, Lilly, Karyopharm, Epizyme, Blueprint, Genmab, CBA Pharma, Philogen, Gradilis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen, Bavarian Nordic, BTG Pharmaceuticals, PTC Therapeutics, GSK, Forma Therapeutics, Ayala Pharma, Trillium, Boehringer Ingelheim, Salarius, Theseus, Monopar, C4 Therapeutics, Inhibrx, Noxopharm, Rain Therapeutics, Shanghai Pharma, PharmaMar, Cogen, and Jazz Therapeutics. SA reports grant funding to himself from Guardant. EC reports consulting fees from Sonata Therapeutics, Adaptimmune, Epizyme, and Bayer; and participation in advisory boards for Adaptimmune and Pfizer. DIP reports honoraria for presentations to Bayer. BAVT reports grant funding from Polaris; a patent on ALEXT3102; a patent on the use of ME1 as a biomarker; licences from Accuronix Therapeutics; consulting fees from Cytokinetics, Bayer, Deciphera Pharmaceuticals, Daiichi Sankyo, EcoR1, Advenchen, Putnam, Salarius Pharmaceuticals, Boxer Capital, Acuta Capital Partners, Aadi Bioscience, Race Oncology, Kronos Bio, Sonata Therapeutics, and Hinge Bio; honoraria for presentations from Iterion Therapeutics, and Total Health Conference; travel support from Adaptimmune, Advenchen Laboratories, Polaris, and Kronos Bio; participation in advisory boards for Apexigen, Daiichi Sankyo, Epizyme, Bayer US Medical Affairs Oncology, PTC Therapeutics, Asdi Biosciences, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals, Curis; and an unpaid role on the safety monitoring board for Polaris. GT reports receiving payment for participating on an advisory board for Servier and consulting fees from Daiichi Sankyo. BC reports funding paid to the institution by SARC for support of this study; grant funding for clinical trial support paid to the institution by Bristol Myers Squibb, Macrogenics, Karyopharm Therapeutics, Infinity Pharmaceuticals, Advenchen Laboratories, Xencor, Compugen, Iovance, RAPT Therapeutics, IDEAYA Biosciences, Ascentage, Atreca, Replimune, Instil Bio, Adagene, TriSalus Life Sciences, Kinnate, PTC Therapeutics, Xilio Therapeutics, Kezar Life Sciences, and Immunocore; payment for participation on advisory boards at Novartis, Delcath, Instil Bio, Replimune, Atreca, Regeneron, and Treeline Biosciences; and payment for participation on the data monitoring committee for SpringWorks Therapeutics. AG reports funding to the institution from PharmaMar and Nanobiotix; consulting fees from Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks, and Boehringer Ingelheim; honoraria for presentations from PharmaMar and Deciphera; travel support from PharmaMar; and leadership roles as the International Representative on the Executive Council of the Society of Surgical Oncology, a member of the Board of Directors of the European Society of Surgical Oncology, and a member of the Board of Directors of the Italian Sarcoma Group. CFM reports consulting fees for participating on advisory boards for Deciphera, Daiichi Sankyo, and Aadi Bioscience. MAD reports funding to the institution from Eli Lilly, Sumitomo Pharma, and Aadi Bioscience. LED reports funding from SARC to the institution to support this study; funding to the institution for clinical trial activities from Salarius, Inhibrx, BioAtla, Adaptimmune, GSK, SpringWorks, Epizyme, BTG Pharmaceuticals, Eisai, and Novartis; consulting fees from GLG Expert Network and Guidepoint Expert Network; educational payment from SpringWorks; payment for participating on advisory boards for Daiichi Sankyo, Inhibrx, Regeneron, and SpringWorks; leadership role on the scientific steering committee for SARC; leadership role on the scientific advisory board for the Osteosarcoma Institute; and a former leadership role on the Northwest Sarcoma Foundation Board of Directors. BEB reports consulting fees from Daiichi Sankyo, Deciphera, and Musculoskeletal Transplant Foundation; participation on a data safety monitoring board for PARITY Trial and SAFETY trial; and serving as a member of the Executive Board for the Musculoskeletal Tumor Society. RFR reports funding to the institution for clinical trial support from Aadi Bioscience, Adaptimmune, AROG, Ayala, BioAtla, Blueprint, Cogent, Daiichi-Sankyo, Deciphera, GlaxoSmithKline, InhibRx, NanoCarrier, Oncternal, PTC Therapeutics, SARC, SpringWorks, TRACON, and Trillium; consulting fees from Aadi Bioscience, Adaptimmune, Bayer, Blueprint, Boehringer Ingelheim, Daiichi-Sankyo, Deciphera, GSK, NanoCarrier, and SpringWorks; honoraria for lectures from SpringWorks; travel support for advisory board participation for Deciphera; leadership role as co-chair of the ECOG-ACRIN Sarcoma Working Group; medical writing assistance from Prescott Medical Communications Group with financial support from SpringWorks Therapeutics; and spouse ownership in Limbguard. DGK reports funding from MSD through the Merck Investigator Studies Program to the institution to support this study; and grant funding to the institution from Bristol Myers Squibb, Varian Medical Systems, the National Institutes of Health, and the Department of Defense. DGK has a licence for an imaging device through Lumicell; patents through Lumicell and XRad Therapeutics; membership on the scientific advisory board of Lumicell; membership on the independent data monitoring committee for the clinical trial SARCO; previous leadership role as the Councillor in Medicine on the Board of Directors of the International Association for Radiation Research; and holding stock in XRad Therapeutics and Lumicell. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)