Background and aim Proton pump inhibitors (PPIs) are among the most commonly prescribed medications in the US, but their safety in cirrhosis has recently been questioned. We performed a meta-analysis of observational studies to evaluate the impact of PPIs on adverse clinical outcomes in the setting of chronic liver disease (CLD). Methods We searched several databases from inception to 26 May 2019 to identify comparative studies evaluating the effect of PPIs in CLD. Outcomes of interest were the associations between PPIs use and the occurrence of hepatic encephalopathy, hepatocellular carcinoma, spontaneous bacterial peritonitis, bacterial infections, and mortality in CLD. We performed a meta-analysis in accordance to the PRISMA guidelines. Results Of 14,662 papers evaluated, 47 studies with 169,806 participants were identified. Of these, 35 were cohort studies and 12 were case-control studies. The pooled odds ratio (OR) for hepatic encephalopathy in individuals with PPI users, compared with those without, was 2.31 (95% CI 1.63-3.28). The pooled OR for spontaneous bacterial peritonitis in individuals with PPI users was significantly higher compared with non-PPI users (OR = 1.72, 95% CI 1.42-2.09). Results were also consistent with a higher risk of the bacterial infections and mortality in PPI users compared with non-PPI users. For hepatocellular carcinoma, the final conclusion cannot be drawn because of the limited number of studies. Conclusions This study identifies a significant relationship between PPIs therapies and several specific adverse clinical outcomes in CLD. However, these results should be carefully considered given the potential selection bias and unmeasured confounding variables in observational studies, it may be reasonable to re-evaluate the need for PPIs in patients with CLD.