The phase3 PROVENT and STORM CHASER studies evaluated AZD7442 (tixagevimab/cilgavimab) for pre-exposure and post-exposure prophylaxis of symptomatic coronavirus disease 2019 (COVID-19). We report the final 15-month results of both studies. In PROVENT, participants were randomized 2:1 to receive 300mg AZD7442 (n = 3460) or placebo (n = 1737). In STORM CHASER, participants were enrolled within 8days of exposure to a severe acute respiratory syndrome coronavirus2 (SARS-CoV-2)-infected individual and randomized 2:1 to receive 300mg AZD7442 (n = 749) or placebo (n = 372). In PROVENT, the relative risk reduction (RRR) in symptomatic COVID-19 for AZD7442 versus placebo was 76.7% at primary analysis [95% confidence interval (CI) 46.1, 90.0; p < 0.001], 83.0% at day183 (95%CI 67.3, 91.2; nominal p < 0.001), and 46.3% at day366 (95%CI 23.1, 62.4; nominal p < 0.001). Severe/critical COVID-19 was reduced by 91.4% with AZD7442 versus placebo by day366 (95%CI 61.3, 98.1; nominal p < 0.0001). Adverse events (AEs) occurred in 58.2% and 58.0% of participants administered AZD7442 or placebo, respectively; serious AEs (SAEs) occurred in 6.2% and 5.6%, respectively. In STORM CHASER, the RRR in symptomatic COVID-19 for AZD7442 versus placebo was 33.3% at primary analysis (95%CI - 25.9, 64.7; p = 0.212), 43.3% at day183 (95%CI 1.4, 67.4; nominal p = 0.044) and 3.4% at day366 (95%CI - 35.6, 31.2; nominal p = 0.842). Severe/critical COVID-19 did not occur in participants receiving AZD7442 versus 0.5% of participants receiving placebo by day366. AEs occurred in 46.5% and 51.9% of participants administered AZD7442 or placebo, respectively; SAEs occurred in 2.7% and 4.3%, respectively. In both studies, serum concentration-time profiles over 457days were similar for tixagevimab and cilgavimab and consistent with the extended half-life reported for AZD7442 (approximately 90days). This analysis provides proof of concept supporting long-term safety of intramuscularly administered AZD7442 for prevention of symptomatic/severe COVID-19. A graphical abstract is available with this article. PROVENT (NCT04625725) and STORM CHASER (NCT04625972).