Purpose To determine the impact of using sucralfate versus H2RAs for SUP on patient important outcomes. Materials and methods We searched CENTRAL, MEDLINE, EMBASE, ACPJC, clinical trials registries, and conference proceedings through June 2016 for randomized controlled trials (RCTs) comparing sucralfate to H2RAs for SUP in adult critically ill patients. Results 21 RCTs enrolling 3121 patients met inclusion criteria. There was no significant difference between sucralfate compared to H2RAs in the risk of clinically important GI bleeding (risk ratio [RR] 1.19; 95% CI [confidence interval] 0.79, 1.80; P = 0.42; I² = 0%; low quality evidence). However, there was a statistically significant lower risk of ICU acquired pneumonia with sucralfate compared to H2RAs (RR 0.84; 95% CI 0.72, 0.98; P = 0.03; I² = 0%; moderate quality evidence). Sucralfate did not significantly affect the risk of death (RR 0.95; 95% CI 0.82, 1.10; P = 0.51; I² = 0%; high quality evidence), or duration of ICU stay in days (mean difference − 0.39; 95% CI [− 1.12, 0.34]; P = 0.29; I² = 0%; moderate quality evidence). Trial sequential analysis adjusted estimates were consistent with conventional estimates. Conclusion Moderate quality evidence suggests that sucralfate reduced ICU acquired pneumonia compared to H2RAs in adult critically ill patients, with no significant impact on GI bleeding or death.