Little data is available regarding the incidence of gastrointestinal bleeding in adults hospitalized with COVID-19 infection and the influence of patient comorbidities and demographics, COVID-19 therapies, and typical medications used.In this retrospective study, we utilized the National COVID Cohort Collaborative to investigate the primary outcome of the development of gastrointestinal bleeding in 512 467 hospitalized US adults (age >18 years) within 14 days of a COVID-19 infection and the influence of demographics, comorbidities, and selected medications.Gastrointestinal bleeding developed in 0.44% of patients hospitalized with COVID-19. Comorbidities associated with gastrointestinal bleeding include peptic ulcer disease (adjusted odds ratio [aOR] 10.2), obesity (aOR 1.27), chronic kidney disease (aOR 1.20), and tobacco use disorder (aOR 1.28). Lower risk of gastrointestinal bleeding was seen among women (aOR 0.76), Latinx (aOR 0.85), and vaccinated patients (aOR 0.74). Dexamethasone alone or with remdesivir was associated with lower risk of gastrointestinal bleeding (aOR 0.69 and aOR 0.83, respectively). Remdesivir monotherapy was associated with upper gastrointestinal bleeding (aOR 1.25). Proton pump inhibitors were more often prescribed in patients with gastrointestinal bleeding, likely representing treatment for gastrointestinal bleeding rather than a risk factor for its development.In adult patients hospitalized with COVID-19, the use of dexamethasone alone or in combination with remdesivir is negatively associated with gastrointestinal bleeding. Remdesivir monotherapy is associated with increased risk of upper gastrointestinal bleeding.