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Background The prevention of coronavirus disease 2019 (COVID-19) in vulnerable populations is a global health priority. EVADE was a phase 2/3 multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended–half-life monoclonal antibody, for postexposure (PEP) and pre-exposure prophylaxis (PrEP) of symptomatic COVID-19. Methods Eligible participants (vaccine-naive, aged ≥12 years) were randomized 1:1 to receive a single 300-mg intramuscular injection of adintrevimab or placebo. Primary efficacy end points were reverse transcription polymerase chain reaction (RT-PCR)–confirmed symptomatic COVID-19 through day 28 in the PEP cohort (RT-PCR-negative at baseline) and through month 3 in the PrEP cohort (RT-PCR-negative and seronegative at baseline) among participants randomized before emergence of the severe acute respiratory syndrome coronavirus 2 Omicron variant (November 30, 2021). Safety was assessed through 6 months. Results Between April 27, 2021, and January 11, 2022, 2582 participants were randomized. In the primary efficacy analysis, RT-PCR-confirmed symptomatic COVID-19 occurred in 3/175 (1.7%) vs 12/176 (6.8%) adintrevimab- and placebo-treated PEP participants, respectively (74.9% relative risk reduction [RRR]; standardized risk difference, −5.0%; 95% CI, −8.87% to −1.08%; P =.0123) and in 12/752 (1.6%) vs 40/728 (5.5%) adintrevimab- and placebo-treated PrEP participants, respectively (71.0% RRR; standardized risk difference, −3.9%; 95% CI, −5.75% to −2.01%; P <.0001). In a prespecified exploratory analysis of 428 PrEP participants randomized after the emergence of Omicron, adintrevimab reduced RT-PCR-confirmed symptomatic COVID-19 by 40.6% (standardized risk difference −8.4%; 95% CI, −15.35% to −1.46%; nominal P =.0177) vs placebo. Adintrevimab was well tolerated, with no serious drug-related adverse events reported. Conclusions A single intramuscular injection of adintrevimab provided prophylactic efficacy against COVID-19 due to susceptible variants without safety concerns. Clinical trial registration. NCT04859517. [ABSTRACT FROM AUTHOR]