Laboratory-based findings suggest that Sotrovimab is significantly less effective against emerging CARS-CoV-2 variants, however, clinical data is lacking. Here we examined the effectiveness of sotrovimab, in preventing emergency department (ED) presentation and subsequent hospitalization in high-risk subgroups of patients during the SARS-CoV-2 Delta and Omicron waves in Western Sydney, Australia (n = 515). Risk for ED attendance was comparable in Omicron patients, whether BA.1 or BA.2, compared to Delta patients (hazard ratio of 0.97 [0.36-2.64]). These findings highlight the need for caution when using in vitro findings to drive clinical practice, especially when the consequence is to withhold potentially lifesaving treatment.