One of the major side effects of nonsteroidal antiinflammatory drugs, such as indomethacin, is gastropathy. The purpose of this study was to search for a therapeutic drug to prevent this side effect in vitro. We found that geranylgeranylacetone, a unique antiulcer drug with a heat-shock protein-inducing ability, protected cultured guinea pig gastric mucosal cells from cell damage caused by indomethacin. This cytoprotective effect of geranylgeranylacetone required concentrations of more than 10(-6) M and incubation periods of longer than 2 hr. Pretreatment of cells with an inhibitor of protein synthesis completely abolished the cytoprotective effect of geranylgeranylacetone, suggesting that some proteins induced by the drug are responsible for the cytoprotection. Since pretreatment of cells with low concentrations of ethanol, which also induced the heat-shock proteins, made cells resistant to indomethacin, heat-shock proteins are candidates for the proteins that are involved in the cytoprotective effect of geranylgeranylacetone against indomethacin.