Proton pump inhibitors (PPIs) were first introduced in the market in the 1980s and are used as an over-the-counter (OTC) drug for acid-related diseases of the gastrointestinal tract. (1) Over the years, both prescription and non-prescription use of PPIs has grown exponentially, and they are now among the most widely used class of drugs globally. (2) PPIs are generally intended for short-term use and are rarely required beyond four to eight weeks; however, in real-world practice, their duration of use often extends beyond recommended guidelines. Hepatocellular carcinoma (HCC), a primary liver cancer, is a heterogeneous disease with multiple variables that differ by geography and presence or absence of prognostic factors such as NAFLD and cirrhosis. Preclinical studies have found PPIs-induced acid suppression to be associated with disease progression in hepatic diseases such as alcoholic liver disease, NAFLD, non-alcoholic steatohepatitis, and liver tumors. Similarly, population-based studies have also found an association of PPIs use with the risk of acute liver injury. (3) Nevertheless, many recent pharmacoepidemiologic studies using real-world databases to evaluate the association between PPIs and the risk of HCC show divergent results. (4-6) Thus, a systematic review was conducted to identify all the published articles and to determine the effect of PPI on the risk of HCC based on real-world data studies.