In this study, we examined adaptive cytoprotection against NSAIDs in human gastric carcinoma cells in culture. Pretreatment of cells with low (nontoxic) concentrations of ethanol protected cells from cell death induced by subsequent exposure to NSAIDs. The adaptive cytoprotection against NSAIDs induced by ethanol was not attenuated by pretreatment of cells with inhibitors of protein synthesis or prostaglandin synthesis, thus inferring that neither newly synthesized proteins nor prostaglandins are involved in this process. Furthermore, treatment of cells with the low concentration of ethanol did not affect the synthesis and secretion of mucin. In in vivo experiments on rats, oral preadministration of a low dose of ethanol protected the gastric mucosa from gastric lesions induced by subsequent oral administration of NSAIDs. One possible explanation for this in vivo phenomenon is that the adaptive cytoprotection induced by ethanol protects the gastric mucosa from the direct cytotoxic effect of NSAIDs.