BackgroundImmune-evading severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are emerging continuously. The clinical effectiveness of monoclonal antibody agents that exhibit decreasedin vitroactivity against SARS-CoV-2 variants needs to be elucidated.MethodsA nationwide, multicenter, retrospective cohort study was designed to evaluate the effectiveness of regdanvimab, an anti-SARS-CoV-2 monoclonal antibody agent. Regdanvimab was prescribed in South Korea before and after the emergence of the delta variant, against which thein vitroactivity of regdanvimab was decreased but present. Mild to moderate coronavirus 2019 (COVID-19) patients with risk factors for disease progression who were admitted within seven days of symptom onset were screened in four designated hospitals between December 2020 and September 2021. The primary outcomes, O2requirements and progression to severe disease within 21 days of admission, were compared between the regdanvimab and supportive care groups, with a subgroup analysis of delta variant–confirmed patients.ResultsA total of 2,214 mild to moderate COVID-19 patients were included, of whom 1,095 (49.5%) received regdanvimab treatment. In the analysis of the total cohort, significantly fewer patients in the regdanvimab group than the supportive care group required O2support (18.4% vs. 27.1%,P< 0.001) and progressed to severe disease (4.0% vs. 8.0%,P< 0.001). In the multivariable analysis, regdanvimab was significantly associated with a decreased risk for O2support (HR 0.677, 95% CI 0.561–0.816) and progression to severe disease (HR 0.489, 95% CI 0.337–0.709). Among the 939 delta-confirmed patients, O2support (21.5% vs. 23.5%,P= 0.526) and progression to severe disease (4.2% vs. 7.3%,P= 0.055) did not differ significantly between the regdanvimab and supportive care groups. In the multivariable analyses, regdanvimab treatment was not significantly associated with a decreased risk for O2support (HR 0.963, 95% CI 0.697–1.329) or progression to severe disease (HR 0.665, 95% CI 0.349–1.268) in delta-confirmed group.ConclusionsRegdanvimab treatment effectively reduced progression to severe disease in the overall study population, but did not show significant effectiveness in the delta-confirmed patients. The effectiveness of dose increment of monoclonal antibody agents should be evaluated for variant strains exhibiting reduced susceptibility.