<p>We have previously found using questionnaire/interview data on COVID-19 outcomes, that most subjects with severe alpha-1-antitrypsin deficiency (AATD) exhibit mild COVID-19 infection and those who additionally have COPD are at increased risk of severe COVID-19. We used objective information on COVID-19 outcomes in severe AATD (PiZZ) from the Swedish population and compared the risk of severe COVID-19 in severe AATD to the risk of severe COVID-19 in the general population. We cross-linked the Swedish National AATD Registry with the Swedish National Patient Register to identify subjects with severe AATD that required COVID-19-related hospitalization between March 2020 until June 2023. Standardised incidence ratio (SIR) was calculated using observed COVID-19 hospitalisations in severe AATD and expected COVID-19 hospitalisations from the general population. Logistic regression was used to calculate odds of moderate or severe COVID-19 in severe AATD in relation to pre-existing comorbidities. In 1228 subjects with severe AATD, there were 61 cases of COVID-19-related hospitalisations (severe COVID-19) and 32 moderate COVID-19 during follow-up. The observed hospitalizations for COVID-19 in subjects with severe AATD exceeded that expected in the general population by over threefold (SIR = 3.4). Odds of COVID-19 was elevated in subjects with severe AATD with COPD or CVD (OR 2.70 (1.52–4.80) and 3.51 (2.04–6.06), respectively. The majority of subjects with severe AAT deficiency had mild COVID-19 during the pandemic. Of subjects that did have severe COVID-19, pre-existing co-morbidities were common, potentially explaining the higher rate of COVID-19 hospitalisations in severe AATD relative to the general population.</p>