Proton pump inhibitors (PPIs) are novel compounds that strongly inhibit the H(+)/K(+)-ATPase in the gastric parietal cells to cause profound suppression of acid secretion. Acid-generating ATPase, also known as vacuolar-type ATPase, is located in the lysozomes of leukocytes and osteoclasts and its activity is also reportedly influenced by treatment with PPIs. This concept is supported by the results of studies using autoradiography in which (3)H-Lansoprazole uptake sites were clearly detected in the cytoplasmic granules of neutrophils infiltrating the gastric mucosa. In vitro studies indicate that PPIs increase the intra-vacuolar pH in the lysosomes of purified neutrophils and attenuate the adherence of neutrophils to the vascular endothelium. In clinical practice, the acidic environment in the stomach plays a critical role in the development of gastritis induced by Helicobacter pylori (H. pylori). This is worthy of note, because persistent gastritis often results in atrophic and metaplastic changes in the gastric mucosa, which are believed to be preneoplastic abnormalities. In patients with H. pylori-infection, PPI therapy causes corpus-predominant gastritis, which is frequently found in the background mucosa in patients with gastric cancer. The efficacy and safety of long-term PPI-treatment have not been conclusive, thus we need to pay more attention to the additional pharmacological actions of PPIs.