Although the incidence of gastric cancer varies widely between countries it is nonetheless a leading cause of cancer deaths worldwide. Migration studies indicate that dietary choices are an important exogenous factor. The United States has a very low incidence of gastric cancer, suggesting that exogenous etiological agents are at a minimum and providing a favorable setting for detecting important endogenous etiological factors. Dehydroepiandrosterone and dehydroepiandrosterone sulfate are endogenous steroids produced in the adrenal gland. Epidemiological studies show that the risk of developing specific cancers is related to the serum or urinary levels of these steroids. In addition, dehydroepiandrosterone prevents a variety of spontaneous and chemically induced tumors when administered to laboratory animals. To examine the association between circulating levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate and the development of gastric cancer, we measured the serum levels of these steroids in 13 individuals who donated serum to the Washington County Maryland serum bank in 1974 and who subsequently developed gastric cancer and in 52 matched controls. Prediagnostic serum levels of dehydroepiandrosterone were 38% lower in cases as compared to controls (P = 0.09). The risk of developing gastric cancer increased with decreasing levels of both steroids. Adjustment for confounding factors such as smoking or the interval between blood donation and time to diagnosis did not alter the findings. These results suggest that there may be a role for this steroid in the prevention of gastric cancer.