Abstract Despite the lightning-fast advances in the management of SARS-CoV after 2 years of pandemic, COVID-19 continues to pose a challenge for fragile patients, who could benefit from early administration of monoclonal antibodies (mAbs) to reduce the risk of severe disease progression. We conducted a prospective study to evaluate effectiveness of mAbs against SARS-CoV-2 among patients at risk for severe disease progression, namely elderly and those with comorbidities, before the omicron variant surge. Patients were treated with either casirivimab/imdevimab, sotrovimab, and bamlanivimab/etesevimab. The rates and risk factos for clinical worsening, hospitalization, ICU admission and death (unfavourable outcomes) were evaluated. A stratified analysis according to the presence of SARS-CoV-2 IgG was also performed. Among 185 included patients, we showed low rates of unfavorable outcomes (9.2%), which were more frequent in patients with chronic kidney disease (aOR: 10.44, 95CI: 1.73-63.03; p<0.05) and basal D-dimer serum concentrations >600 ng/ml (aOR 21.74, 95CI: 1.18-397.70; p<0.05). Patients with negative SARS-CoV-2 serology at baseline showed higher C-reactive protein values compared with patients with positive serology (p <0.05) and showed a trend toward a higher admission rate to SICU and ICU compared with patients with positive serology. Our results thus showed, in a real-life setting, the efficacy of mAbs against SARS-CoV-2 before Omicron surge when the available mabs become not effective.