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Objectives: We aimed to use setting-appropriate comparisons to estimate the effects of different gastrointestinal (GI) prophylaxis pharmacotherapies for patients hospitalized with COVID-19 and setting-inappropriate comparisons to illustrate how improper design choices could result in biased results., Study Design and Setting: We identified 3,804 hospitalized patients aged ≥ 18 years with COVID-19 from March to November 2020. We compared the effects of different gastroprotective agents on clinical improvement of COVID-19, as measured by a published severity scale. We used propensity score-based fine-stratification for confounding adjustment. Based on guidelines, we prespecified comparisons between agents with clinical equipoise and inappropriate comparisons of users vs. nonusers of GI prophylaxis in the intensive care unit (ICU)., Results: No benefit was detected when comparing oral famotidine to omeprazole in patients treated in the general ward or ICUs. We also found no associations when comparing intravenous famotidine to intravenous pantoprazole. For inappropriate comparisons of users vs. nonusers in the ICU, the probability of improvement was reduced by 32%-45% in famotidine users and 21%-48% in omeprazole or pantoprazole users., Conclusion: We found no evidence that GI prophylaxis improved outcomes for patients hospitalized with COVID-19 in setting-appropriate comparisons. An improper comparator choice can lead to spurious associations in critically ill patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)