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Background: Accumulating evidence indicates that an early, robust type 1 interferon (IFN) response to SARS-CoV-2 is important in determining COVID-19 outcomes, with an inadequate IFN response associated with disease severity. Our objective was to examine the prophylactic potential of IFN administration to limit viral transmission., Methods: A cluster randomised open label clinical trial was undertaken to determine the effects of pegylated IFNβ-1a administration on SARS-CoV-2 household transmission between December 3rd, 2020 and June 29th, 2021. Index cases were identified from databases of confirmed SARS-CoV-2 individuals in Santiago, Chile. Households were cluster randomised (stratified by household size and age of index cases) to receive 3 doses of 125 μg subcutaneous pegylated IFNβ-1a (172 households, 607 participants), or standard care (169 households, 565 participants). The statistical team was blinded to treatment assignment until the analysis plan was finalised. Analyses were undertaken to determine effects of treatment on viral shedding and viral transmission. Safety analyses included incidence and severity of adverse events in all treatment eligible participants in the standard care arm, or in the treatment arm with at least one dose administered. Clinicaltrials.gov identifier: NCT04552379., Findings: 5154 index cases were assessed for eligibility, 1372 index cases invited to participate, and 341 index cases and their household contacts (n = 831) enrolled. 1172 participants in 341 households underwent randomisation, with 607 assigned to receive IFNβ-1a and 565 to standard care. Based on intention to treat (ITT) and per protocol (PP) analyses for the primary endpoints, IFNβ-1a treatment did not affect duration of viral shedding in index cases (absolute risk reduction = -0.2%, 95% CI = -8.46% to 8.06%) and transmission of SARS-CoV-2 to household contacts (absolute risk reduction = 3.87%, 95% CI = -3.6% to 11.3%). Treatment with IFNβ-1a resulted in significantly more treatment-related adverse events, but no increase in overall adverse events or serious adverse events., Interpretation: Based upon the primary analyses, IFNβ-1a treatment did not affect duration of viral shedding or the probability of SARS-CoV-2 transmission to uninfected contacts within a household., Funding: Biogen PTY Ltd. Supply of interferon as 'Plegridy (peginterferon beta-1a).' The study was substantially funded by BHP Holdings Pty Ltd., Competing Interests: Authors Castro-Rodriguez, Kollman, and Stick received funding from BHP Holdings Pty Ltd and Biogen Pty Ltd to conduct this study. Balshaw was paid consulting fees to advise on this study. Castro-Rodriguez received honoraria from AstraZeneca and GlaxoSmithKline to speak at symposia and Eurofarma for participation on advisory board. Kollmann has received research funding from NIH, Medical Research Future Fund, and Bill and Melinda Gates Foundation, honoraria from the Human Immunome Project to attend a conference, and holds two patents unrelated to this study. Montgomery received funding from NHMRC and TSANZ to present findings from this study at conferences. Authors Aniba, Borzutzky, Chen, Fish, Garcia-Huidobro, Gigi-Yunge, Hancock, Hartnell, Ho, Iturriaga, Karpievitch, Othman, Perret, Shannon, Tebbutt, and Urzua have no declared conflicts of interest., (© 2023 The Author(s).)