Abstract Background The SARS-CoV-2 variant B.1.1.529 (Omicron) was first described in November 2021 and became the dominant variant worldwide. Existing data suggests a reduced disease severity with Omicron infections in comparison to B.1.617.2 (Delta). Differences in characteristics and in-hospital outcomes of COVID-19 patients in Germany during the Omicron period compared to Delta are not thoroughly studied. ICD-10-code-based severe acute respiratory infections (SARI) surveillance represents an integral part of infectious disease control in Germany. Methods Administrative data from 89 German Helios hospitals was retrospectively analysed. Laboratory-confirmed SARS-CoV-2 infections were identified by ICD-10-code U07.1 and SARI cases by ICD-10-codes J09-J22. COVID-19 cases were stratified by concomitant SARI. A nine-week observational period between December 6, 2021 and February 6, 2022 was defined and divided into three phases with respect to the dominating virus variant (Delta, Delta to Omicron transition, Omicron). Regression analyses adjusted for age, gender and Elixhauser comorbidities were applied to assess in-hospital patient outcomes. Results A total cohort of 4,494 inpatients was analysed. Patients in the Omicron dominance period were younger (mean age 47.8 vs. 61.6; p < 0.01), more likely to be female (54.7% vs. 47.5%; p < 0.01) and characterized by a lower comorbidity burden (mean Elixhauser comorbidity index 5.4 vs. 8.2; p < 0.01). Comparing Delta and Omicron periods, patients were at significantly lower risk for intensive care treatment (adjusted odds ratio 0.72 [0.57–0.91]; p = 0.005), mechanical ventilation (adjusted odds ratio 0.42 [0.31–0.57]; p < 0.001), and in-hospital mortality (adjusted odds ratio 0.42 [0.32–0.56]; p < 0.001). This also applied mostly to the separate COVID-SARI group. During the Delta to Omicron transition, case numbers of COVID-19 without SARI exceeded COVID-SARI for the first time in the pandemic’s course. Conclusion Patient characteristics and outcomes differ during the Omicron dominance period as compared to Delta suggesting a reduced disease severity with Omicron infections. SARI surveillance might play a crucial role in assessing disease severity of future SARS-CoV-2 variants.