ObjectivesTo investigate:(1) the risk of severe COVID-19 in those eligible for shielding, and (2) the relation of severe COVID-19 to transmission-related factors in those in shielding and the general population.DesignMatched case-control study (REACT-SCOT).SettingPopulation of Scotland from 1 March 2020 to 28 January 2021.ParticipantsAll 160307 diagnosed cases of COVID-19 and 1564782 controls matched for age, sex and primary care practice, linked with all 204913 individuals identified as eligible for shielding by Public Health Scotland.Main outcome measureSevere COVID-19, defined as cases that entered critical care or were fatal.ResultsWith those without risk conditions as reference category, the univariate rate ratio for severe COVID-19 was 5.3 (95% CI 5.0 to 5.7, p=4 × 10−527) in those with moderate risk conditions and 7.6 (95% CI 7.1 to 8.3, p=1 × 10−527) in those eligible for shielding. The highest rate was in solid organ transplant recipients: rate ratio 13.6 (95% CI 9.6 to 19.2, p=8 × 10−50). In both the shielded and the general population, the risk of severe COVID-19 increased with the number of adults but decreased with the number of school-age children in the household. Severe COVID-19 was strongly associated with recent exposure to hospital (defined as 5 to 14 days before presentation date): rate ratio 12.6 (95% CI 11.7 to 13.6, p=2 × 10−989) overall. In a case-crossover analysis with less recent exposure only (15 to 24 days before first testing positive) as reference category, the rate ratio associated with recent exposure only was 6.3 (95% CI 3.6 to 11.1, p=2 × 10−10). Among those eligible for shielding, the population attributable risk fraction (PARF) of severe cases for recent exposure to hospital was 36%. In the general population the PARF for recent exposure to hospital peaked at 46% in May 2020 and again at 64% in December 2020.ConclusionsThe effectiveness of shielding vulnerable individuals was limited by the inability to control transmission in hospital and from other adults in the household. For solid organ transplant recipients, in whom the efficacy of vaccines is uncertain, these results support a policy of offering vaccination to household contacts. Mitigating the impact of the epidemic requires control of nosocomial transmission.SummaryWhat is already known on this topic?Individuals designated as “clinically extremely vulnerable” – about 3% of the population – have been advised to shield themselves during the COVID-19 epidemicThe effectiveness of this shielding programme has not been evaluated.What this study addsHospital-acquired infection has made a substantial contribution to the burden of COVID-19 in the population, accounting for more than half of severe cases in early December 2020.For vulnerable individuals to be shielded, the risk of hospital-acquired infection must be reduced and support must be provided for other adults in the household to co-isolate with the vulnerable individual.Solid organ transplant recipients are at the highest risk; vaccination of household contacts should be considered for this group.