We conducted a post-hoc analysis in seropositive patients who were negative or borderline for functional neutralizing antibodies (nAbs) against SARS-CoV-2 at baseline from a phase 1/2/3 trial of casirivimab and imdevimab (CAS+IMD) treatment in hospitalized COVID-19 patients on low-flow or no supplemental oxygen prior to the emergence of Omicron-lineage variants. Patients were randomized to a single dose of 2.4 g CAS+IMD, 8.0 g CAS+IMD, or placebo. Patients seropositive for anti-SARS-CoV-2 antibodies at baseline were analyzed by their baseline nAb status. At baseline, 20.6% (178/864) of seropositive patients were negative/borderline for nAbs. CAS+IMD reduced viral load in patients who were negative/borderline for nAbs versus placebo, but not in patients who were positive for nAbs. We observed a trend in reduction of the proportion of patients who died or required mechanical ventilation (MV), as well as in all-cause mortality, by day 29 with CAS+IMD versus placebo in patients who were negative/borderline for nAbs. In those who were negative/borderline for nAbs, the proportions who died/needed MV from days 1-29 were 19.1% and 10.9%, and the proportions of patients who died from days 1-29 were 16.2% and 9.1%, in the placebo and CAS+IMD combined dose groups, respectively. No measurable harm or benefit in death/MV or all-cause mortality was observed in patients who were positive for nAbs. In hospitalized COVID-19 patients on low-flow or no supplemental oxygen, CAS+IMD reduced viral load, the risk of death or MV, and all-cause mortality in seropositive patients who were negative/borderline for nAbs. ImportanceThe clinical benefit of CAS+IMD in hospitalized seronegative patients with COVID-19 has previously been demonstrated, although these studies observed no clinical benefit in seropositive patients. As the prevalence of SARS-CoV-2 seropositive individuals rises due to both vaccination and previous infection, it is important to understand whether there is a subset of hospitalized patients with COVID-19, who have antibodies against SARS-CoV-2, who could benefit from anti-SARS-CoV-2 monoclonal antibody treatment. This post-hoc analysis demonstrates that there is a subset of hospitalized, seropositive patients with inadequate SARS-CoV-2 nAbs (ie, those who were negative or borderline for nAbs) who may still benefit from CAS+IMD treatment if infected with a susceptible variant. Therefore, utilizing seronegativity status alone to guide treatment decisions for patients with COVID-19 may fail to identify seropositive patients who could benefit from anti-SARS-CoV-2 monoclonal antibody therapies which retain activity against circulating strains, depending on how effectively their endogenous antibodies neutralize SARS-CoV-2.