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Background: Biological considerations suggest that renin–angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin–angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. Methods: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin–angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin–angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin–angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. Findings: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin–angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin–angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40–110] for continuation vs 81 [38–117] for discontinuation; β-coefficient 8 [95% CI −13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. Interpretation: Consistent with international society recommendations, renin–angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. Funding: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants. Fil: Cohen, Jordana B.. State University of Pennsylvania; Estados Unidos Fil: Hanff, Thomas C.. State University of Pennsylvania; Estados Unidos Fil: William, Preethi. University of Arizona; Estados Unidos Fil: Sweitzer, Nancy. University of Arizona; Estados Unidos Fil: Rosado Santander, Nelson R.. Hospital Nacional Carlos Alberto Seguin Escobedo; Perú Fil: Medina, Carola. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: Rodriguez-Mori, Juan E. Hospital Nacional Alberto Sabogal Sologuren; Perú Fil: Renna, Nicolas Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo; Argentina Fil: Chang, Tara I.. University of Stanford; Estados Unidos Fil: Corrales Medina, Vicente. Ottawa Hospital Research Institute; Canadá Fil: Andrade Villanueva, Jaime F.. Hospital Civil de Guadalajara; México Fil: Barbagelata, Alejandro. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires"; Argentina. University of Duke; Estados Unidos Fil: Cristodulo Cortez, Roberto. No especifíca; Fil: Díaz-Cucho, Omar A. Hospital Alberto Leopoldo Barton Thompson; Perú Fil: Spaak, Jonas. Danderyd University Hospital; Suecia Fil: Alfonso, Carlos E.. University of Miami; Estados Unidos Fil: Valdivia Vega, Renzo. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: Villavicencio Carranza, Mirko. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: Ayala García, Ricardo J.. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: Castro Callirgos, Carlos A.. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: González Hernández, Luz A.. Hospital Civil de Guadalajara; México Fil: Bernales Salas, Eduardo F.. Hospital Nacional Carlos Alberto Seguin Escobedo; Perú Fil: Coacalla Guerra, Johanna C.. Hospital Nacional Carlos Alberto Seguin Escobedo; Perú Fil: Salinas Herrera, Cynthia D.. Hospital Nacional Carlos Alberto Seguin Escobedo; Perú Fil: Nicolosi, Liliana. Hospital Espanol; Argentina Fil: Basconcel, Mauro. Hospital Espanol; Argentina Fil: Byrd, James B.. University of Michigan; Estados Unidos Fil: Sharkoski, Tiffany. University of Pennsylvania; Estados Unidos Fil: Bendezú Huasasquiche, Luis E.. Hospital Alberto Leopoldo Barton Thompson; Perú Fil: Chittams, Jesse. University of Pennsylvania; Estados Unidos Fil: Edmonston, Daniel L.. University of Duke; Estados Unidos Fil: Vasquez, Charles R.. University of Pennsylvania; Estados Unidos Fil: Chirinos, Julio A.. University of Pennsylvania; Estados Unidos