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During the last years proton pump inhibitors (PPIs), previously regarded as very safe drugs and allowed to be sold over the counter, have been reported to give side effects in many organ systems. However, most of these negative reports probably are due to residual confounding factors. In general, the side effects of PPIs are due to their biological effect in removing the biological effect of gastric juice that is killing microorganisms, and the secondary hypergastrinemia in an unsuccessful attempt to restore normal gastric acidity. Whereas the possibility that hypergastrinemia could predispose to gastric cancer has been permanently on the agenda since the introduction of PPIs, the removal of the important protective effect towards microbes has surprisingly only been focused on during the later years as a consequence of increased interest on the gut microbiome. PPI treatment affects the microbiome, and it exists one report describing increased risk of primary liver cancer due to PPI use. Changes in the gut microbiome have been shown to participate in the pathogenesis of chronic liver diseases caused by ethanol as well as obesity. In general, chronic liver diseases predispose to liver cancer. There are also rodent studies incriminating inhibition of gastric acid secretion in the pathogenesis of primary liver cancer. However, it must be concluded that presently the role of PPIs in the development of primary liver cancer seems weak.