Background The Alpha variant (B.1.1.7 lineage) of SARS-CoV-2 emerged and became the dominant circulating variant in the UK in late 2020. Current literature is unclear on whether the Alpha variant is associated with increased severity. We linked clinical data with viral genome sequence data to compare admitted cases between SARS-CoV-2 waves in London and to investigate the association between the Alpha variant and the severity of disease. Methods Clinical, demographic, laboratory and viral sequence data from electronic health record systems were collected for all cases with a positive SARS-CoV-2 RNA test between 13 March 2020 and 17 February 2021 in a multisite London healthcare institution. Multivariate analysis using logistic regression assessed risk factors for severity as defined by hypoxia at admission. Results There were 5810 SARS-CoV-2 RNA-positive cases of which 2341 were admitted (838 in wave 1 and 1503 in wave 2). Both waves had a temporally aligned rise in nosocomial cases (96 in wave 1 and 137 in wave 2). The Alpha variant was first identified on 15 November 2020 and increased rapidly to comprise 400/472 (85%) of sequenced isolates from admitted cases in wave 2. A multivariate analysis identified risk factors for severity on admission, such as age (OR 1.02, 95% CI 1.01 to 1.03, for every year older; p<0.001), obesity (OR 1.70, 95% CI 1.28 to 2.26; p<0.001) and infection with the Alpha variant (OR 1.68, 95% CI 1.26 to 2.24; p<0.001). Conclusions Our analysis is the first in hospitalised cohorts to show increased severity of disease associated with the Alpha variant. The number of nosocomial cases was similar in both waves despite the introduction of many infection control interventions before wave 2.