To determine whether starvation increases the susceptibility of the gastric mucosa to stress ulceration and whether this effect is linked to a change in the mucosal level of prostaglandin-E2 (PGE2), 100 Holtzman rats were divided into five groups and deprived of food for 0, 12, 24, 48 and 72 h. Then, ten animals within each group were stressed by cold restraint. At the end of the stress period, all these animals as well as their unstressed counterparts were killed, the number of gastric ulcers were counted, and mucosal levels of PGE2 were assayed. Fasting alone caused no ulcerations but a decrease in mucosal PGE2 during the initial 24 h (p less than .05). However, there was a subsequent increase in mucosal PGE2, possibly related to the release of free fatty acids during starvation. Starvation and stress caused a marked and consistent reduction of the mucosal PGE2 and an increase in the number of mucosal ulcerations directly related to the duration of starvation (p less than .05).