Background: The SARS-CoV-2 pandemic has resulted in enormous morbidity and mortality worldwide, yet no medications to date are proven to improve clinical outcomes in hospitalized COVID-19 patients. Famotidine is commonly used for gastric acid suppression but also has recently gained attention as an antiviral that may inhibit SARS-CoV-2 replication. Objective: To determine whether famotidine use is associated with improved clinical outcomes in patients with COVID-19 initially hospitalized to a non-intensive care setting. Design: Retrospective cohort study. Setting: Inpatients at a single academic medical center. Participants: Consecutive hospitalized patients with COVID-19 infection from February 25 to April 13, 2020. Measurements: Famotidine use (exposure); intubation or death (primary outcome) Results: 1,620 hospitalized patients with COVID-19 were analyzed including 84 (5.1%) who received famotidine within 24 hours of hospital admission. There were no differences between famotidine users and non-users in age, body mass index, or comorbidities including diabetes or hypertension. 340 (21%) patients met the study composite outcome of death or intubation. Use of famotidine was associated with reduced risk for death or intubation (adjusted hazard ratio (aHR) 0.40, 95% CI 0.20-0.81) and also with reduced risk for death alone (aHR 0.29, 95% CI 0.11-0.78). Proton pump inhibitors, which also suppress gastric acid, were not associated with reduced risk for death or intubation. In patients without COVID-19 hospitalized during the same time period, no association was observed between use of famotidine and death or intubation. Limitations: Retrospective analysis; non-randomized exposure. Conclusion: Famotidine use is associated with reduced risk of intubation or death in hospitalized COVID-19 patients. Randomized controlled trials are warranted to determine whether famotidine therapy improves outcomes in hospitalized COVID-19 patients.