Neutralizing monoclonal antibodies (mAbs) for pre- and post-exposure prophylaxis of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are largely used to prevent the progression of the disease by blocking viral attachment, host cell entry, and infectivity. Sotrovimab, like other available mAbs, has been developed against the receptor binding Domain of the Spike (S) glycoprotein of the virus. Nevertheless, the latest Omicron variant has shown marked mutations within the S gene, thus opening the question of the efficacy of these neutralizing molecules towards this novel variant. In the present observational study, we describe the effects of Sotrovimab in the treatment of 15 fully vaccinated patients, infected by SARS-CoV-2 Omicron sub-variants, who were selected on the basis of factors widely considered to affect a worse prognosis: immune suppression (n = 12) and/or chronic kidney disease (n = 5) with evidence of interstitial pneumonia in nine patients. The effectiveness of Sotrovimab in the treatment of severe cases of COVID-19 was demonstrated by the regression of symptoms (mean 5.7 days), no need of hospitalisation, improvement of general health conditions and viral clearance within 30 days in all patients. In conclusion, although loss or reduction of mAbs neutralizing activity against the Omicron variant have been described, Sotrovimab has clinically proven to be a safe and useful treatment for patients with high risk of progression to severe COVID-19 infected by Omicron sub-variants.