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Background: There was excess mortality from the first wave of coronavirus 2019 infection (COVID-19), which mainly affected older people. To mitigate risk, the UK government recommended ‘shielding’ of vulnerable people through self-isolation for 12 weeks. We investigated the impact of primary care-reinforced shielding advice on all-cause mortality.Methods: We conducted a retrospective cohort study using a nationally representative English primary care database. We compare people aged >=40years who were recorded as being advised to shield using a fixed ratio of 1:1, matching (a mixture of exact and propensity score matching) to people with the same diagnoses not advised to shield (n=77,360 per group). Time-to-death was compared using Cox regression, reporting the hazard ratio (HR) of mortality between groups. A sensitivity analysis compared exact matched cohorts (n=24,752 shielded, n=61,566 exact matches). Findings: Over the follow-up period, we found a time-varying HR of mortality between groups. In the first 21 days, the mortality risk in people shielding was half those not (HR=0.50, 95%CI:0.41-0.59. p<0.0001). Over the remaining nine weeks, mortality risk was 54% higher in the shielded group (HR=1.54, 95%CI:1.41-1.70, p<0.0001). Beyond the shielding period, mortality risk was over two-and-a-half times higher in the shielded group (HR=2.61, 95%CI:2.38-2.87, p<0.0001).Interpretation: General practitioner-reinforced advice to shield halved the risk of mortality for 21 days compared to those who were not. Mortality risk became higher across the remainder of the shielding period, rising to two-and-a-half times greater post-shielding. Shielding may be beneficial in the next wave of COVID-19.Funding Statement: NIHR School of Primary Care, Public Health EnglandDeclaration of Interests: SdeL is the director of RCGP RSC. He has unrelated projects funded by GSK, Seqirus and has been a member of Global Advisory Boards for Seqirus and Sanofi. FDRH reports personal fees from Novartis and Boehringer Ingelheim and grants from Pfizer. All other authors declare no competing interests.Ethics Approval Statement: The RCGP RSC’s work concerning SARS-CoV-2 has been approved by Public Health England’s Caldicott Guardian Committee as fitting under Regulation 3 of the Health Service Control Patient Information Regulations 2002. The study was approved by RCGP.

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