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BACKGROUND: Influenza causes significant morbidity and mortality despite currently available treatments. Although prior studies suggest that anti-influenza immune plasma may provide benefit, those earlier studies were not designed as definitive trials. We aimed to prospectively evaluate the clinical efficacy of high-titre immune plasma in severe influenza A. METHODS: We conducted a randomised, blinded, controlled, phase 3 trial at 31 U.S. medical centres to assess the efficacy of high-titre anti-influenza plasma with hemagglutination inhibition (HAI) antibody titres of ≥ 1:80 compared to low titre plasma (HAI ≤ 1:10). Hospitalized children and adults with severe influenza A were randomly assigned (2:1) to receive either 2 units high-titre plasma or low-titre control plasma (or paediatric equivalent) and followed for 28 days. High-titre and low titre plasma had the same appearance. Randomization was stratified by severity (in the intensive care unit (ICU), non-ICU hospitalization requiring supplemental oxygen, or non-ICU hospitalization not requiring supplemental oxygen) and age (< 18 years of age, ≥ 18 years of age). The primary endpoint was clinical status as assessed by a 6-point ordinal scale (death, in the ICU, non-ICU hospitalization requiring supplemental oxygen, non-ICU hospitalization not requiring supplemental oxygen, not hospitalized but unable to resume normal activity, not hospitalized with full resumption of normal activity) on Day 7 assessed in a proportional odds model. The primary analysis used a modified intention-to-treat approach, excluding two participants who did not receive plasma. This study is registered with Clinicaltrials.gov number: FINDINGS: The study was conducted between January 2016, and May 2018. Of 200 participants enrolled, 140 met criteria for randomization. This was a relatively ill cohort, with 43% of participants enrolled in the ICU and 70% of the non-ICU patients requiring oxygen. 93% of planned plasma infusions were completed. The study was terminated in July 2018 when independent efficacy analysis revealed low conditional power to show an effect of high-titre plasma even if full accrual (target 150 participants) was achieved. The proportional odds ratio for improved clinical status on Day 7 was 1.22 (95% CI [0.65, 2.29], p=0.54). Forty-seven of 138 (38%) participants experienced a total of 88 SAEs – 32 participants (35%) with 60 SAEs in the high-titre arm, and 15 participants (32%) with 28 SAEs in the low-titre arm. The most common SAEs were for ARDS (affecting 4 participants (4%) vs 2 (4%)), allergic transfusion reactions (2 (2%) vs 2 (4%)), and respiratory distress (3 (3%) vs 0 (0%)). Sixty-five of 138 (47%) participants experienced a total of 183 adverse events - 42 participants (46%) with 126 adverse events in the high-titre arm, and 23 participants (49%) with 57 adverse events in the low-titre arm. The most common AEs were anaemia (affecting 4 participants (3%) vs (2 (4%)) and ARDS (4 (3%) vs 3 (5%)). INTERPRETATION: Despite encouraging results from prior studies, high-titre anti-influenza plasma conferred no statistically significant benefit over non-immune plasma. While this study did not have the precision to rule out a small effect that might be clinically relevant, the benefit is insufficient to justify the use of immune plasma for treating patients with severe influenza A.