BackgroundClinical trials in patients with COVID‐19 have exclusively used self‐ or proxy‐reporting to characterize alcohol consumption. The aim of this study was to measure an objective biomarker of recent alcohol use in patients hospitalized with severe COVID‐19‐associated respiratory failure who were enrolled in an investigational clinical trial to determine the prevalence of alcohol misuse, and to explore the relationship of alcohol use with outcomes.MethodsWe conducted a substudy of patients enrolled in the multicenter, phase 2, adaptive platform design, Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And molecular Analysis in COVID‐19 trial (ClinicalTrials.gov: NCT04488081), conducted at 20 hospital systems across the United States. Three hundred and fifty‐five patients with available red blood cell (RBC) samples and 60‐day follow‐up assessments were included. RBCs were utilized to measure phosphatidylethanol (PEth). Prespecified thresholds of PEth were utilized to stratify patients into groups: low/no alcohol use (PEth < 20 ng/mL), significant alcohol use (PEth 20–200 ng/mL), and heavy alcohol use (PEth ≥ 200 ng/mL).ResultsIn this cohort, 17% of patients met criteria for significant alcohol use, while 4% met criteria for heavy alcohol use. Alcohol misuse was associated with diminished odds for home discharge, though this finding did not achieve statistical significance.ConclusionsIn a cohort of patients with severe COVID‐19 enrolled in a clinical trial, alcohol consumption of two or more standard drinks per day was present among 21%, approximating the proportion of patients with diabetes, and raising the possibility that alcohol consumption alters risk for severe viral pneumonia. Undetected alcohol misuse among clinical trial participants has the potential to influence study outcomes or contribute to adverse events.