Aims: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups. Methods: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors. Results: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant. Conclusion: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization.