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Background To compare the intrinsic virulence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant with the delta variant in hospitalized adults with coronavirus disease 2019 (COVID-19). Methods All adults hospitalized in the Capital Region of Copenhagen with a positive reverse transcription polymerase chain reaction test for SARS-CoV-2 and an available variant determination from 1 September 2021 to 11 February 2022. Data from health registries and patient files were used. Omicron and Delta patients were matched (1:1) by age, sex, comorbidities, and vaccination status. We calculated crude and adjusted hazard ratios (aHRs) for severe hypoxemia and mortality at 30 and 60 days. Results 1,043 patients were included. Patients with Omicron were older, had more comorbidities, were frailer, and more often had three vaccine doses than those with Delta. Fewer patients with Omicron developed severe hypoxemia than those with Delta (aHR, 0.55; 95% confidence interval, 0.38 0.78). Omicron patients exhibited decreased aHR for 30- day mortality compared to Delta (aHR, 0.61; 0.39 0.95). Omicron patients who had received three vaccine doses had lower mortality compared to Delta patients who received three doses (aHR, 0.31;0.16 0.59), but not among those who received two or 0 1 doses (aHR, 0.86; 0.41 1.84 and 0.94; 0.49 1.81 respectively). Similar findings were observed for mortality at 60 days. Similar outcomes were obtained in the analyses of 316 individually matched patients. Conclusions Among adults hospitalized with COVID-19, those with Omicron had less severe hypoxemia and nearly 40% higher 30- and 60-day survival, as compared with those with Delta, mainly driven by a larger proportion of Omicron patients vaccinated with three doses of an mRNA vaccine.