BackgroundLaboratory-based evidence indicates that neutralization of the BA.2 (Omicron) variant by sotrovimab is reduced versus previous SARS-CoV-2 variants. Since there is a lack of real-world data, we investigated whether sotrovimab has reduced clinical efficacy against the BA.2 variant. MethodsWe performed a prospective cohort study using real-world data from 1180 randomly-selected BA.2 variant-infected patients. Follow-up to study endpoints averaged 29 days. For mild cases (not requiring oxygen-supplementation), primary outcomes were requiring O2-supplementation, intensive care unit (ICU) admission or death. For moderate-to-severe COVID-19 cases (requiring oxygen-supplementation other than mechanical ventilation), the primary outcome was ICU admission or death. ResultsPatients in the sotrovimab group (n = 569) and control patients (n = 611) were included. Sotrovimab-treated patients versus controls had reduced risk of death (0.4% vs 6.4%, p < 0.001), need for oxygen supplementation (3.5% vs 12.8%, p < 0.001) and ICU admission (0.2% vs 4.9%, p < 0.001). The adjusted-odds ratio for developing any of these outcomes was 0.090 (95% CI 0.049–0.165, p < 0.001). Subgroup analysis of moderate-to-severe sotrovimab-treated patients versus controls revealed reduced mortality (17.7% vs 37.2%, p = 0.006) and ICU admission (0.0% vs 37.2%, p < 0.001). Adjusted-hazards ratio for death or ICU admission was 0.256 (95% CI 0.111–0.593, p < 0.001). ConclusionSotrovimab was effective in reducing COVID-19 progression risk in high-risk BA.2 variant-infected patients. This finding may alleviate concerns about its clinical efficacy.