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Multiple studies of vaccinated and convalescent cohorts have demonstrated that serum neutralizing antibody (nAb) titers correlate with protection against coronavirus disease 2019 (COVID-19). However, the induction of multiple layers of immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure has complicated the establishment of nAbs as a mechanistic correlate of protection (CoP) and hindered the definition of a protective nAb threshold. Here, we show that a half-life–extended monoclonal antibody (adintrevimab) provides about 50% protection against symptomatic COVID-19 in SARS-CoV-2–naïve adults at serum nAb titers on the order of 1:30. Vaccine modeling results support a similar 50% protective nAb threshold, suggesting that low titers of serum nAbs protect in both passive antibody prophylaxis and vaccination settings. Extrapolation of adintrevimab pharmacokinetic data suggests that protection against susceptible variants could be maintained for about 3 years. The results provide a benchmark for the selection of next-generation vaccine candidates and support the use of broad, long-acting monoclonal antibodies as alternatives or supplements to vaccination in high-risk populations. Correlating protection: Monoclonal antibodies have become an essential component of the SARS-CoV-2 treatment toolkit. However, the serum neutralizing titers necessary for these antibodies to confer protection against symptomatic infection have not been determined. Here, Schmidt et al. studied the protection conferred by a half-life extended monoclonal antibody, adintrevimab, in SARS-CoV-2–naive adults. Serum neutralizing antibody titers of 1:30 were sufficient to confer 50% protection against symptomatic infection in these individuals. These data, in combination with pharmacokinetics studies in humans, suggested that adintrevimab could confer protection against susceptible variants for up to 3 years. Together, these results support the use of half-life extended monoclonal antibodies for SARS-CoV-2 prophylaxis, especially in high-risk populations. —CM [ABSTRACT FROM AUTHOR]