In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation (‘cytokine storm syndrome’), which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (α1-AR) antagonists can prevent cytokine storm syndrome in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n=19,659) and three cohorts with pneumonia (n=423,897). Federated across two ARD cohorts, our main result shows that patients using α1-AR antagonists, as compared to nonusers, had a 40% relative risk reduction for ventilation and dying (p=0.014). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to various sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of α1-AR antagonists ameliorates diseases associated with cytokine storm syndrome, such as COVID-19.