Purpose: Acid-suppressive medications are widely used in noneintensive care unit (non-ICU) patients for stress ulcer (SU) prophylaxis. However, SU prophylaxis in this population is still controversial. The purpose of this study was to systematically evaluate the efficacy and tolerability of these agents for SU prophylaxis in non-ICU patients. Methods: Electronic databases including Cochrane, ClinicalTrials.gov, Ovid-Medline, Embase, Chinese CNKI, and Wanfang Data were systematically searched on July 10, 2019, for randomized controlled trials (RCTs) that evaluated acid-suppressive medications in non-ICU patients. Network meta-analysis and pairwise meta-analysis were performed to calculate odds ratios (ORs) and 95% CIs. A random-effects model was used for generating pooled estimates. The primary outcome was occurrence of SU bleeding, and the adverse drug events (ADEs) were described as the secondary outcome. Findings: A total of 17 RCTs involving 1985 patients were eligible. Meta-analysis results indicated that the occurrence of SU bleeding was significantly decreased with all acid-suppressive medications compared with placebos (gastric mucosa protectants, OR = 0.29 [95% CI, 0.14-0.61]; H2-receptor antagonists, OR = 0.3 [95% CI, 0.18-0.50]; proton pump inhibitors [PPIs]: OR = 0.08 [95% CI, 0.04-0.16]). The occurrence of SU bleeding was significantly decreased with PPIs compared with gastric mucosa protectants (OR = 0.29; 95% CI, 0.12-0.72) and H2-receptor antagonists (OR = 0.28; 95% CI, 0.16-0.48). There was no significant difference between any 2 classes of PPIs on SU bleeding or any 2 acid-suppressive medications on ADEs. (C) 2020 Elsevier Inc. All rights reserved.