The effect of acute and chronic alcohol ingestion on the PGE2 synthesis and PGE2 content in the duodenum and ileum was studied in rats. Following a single oral load of 20% alcohol (v/v; 4 g/kg body weight) the synthesis of PGE2 in isolated microsomes from both parts of the small intestine did not differ from that in control rats during the first 8 hours, but was increased significantly after 24 hours. Feeding a liquid diet containing alcohol (37% of total calories) for 1 week led to enhanced PGE2 synthesis in the duodenum. After feeding the diet for 6 and 12 weeks the rate of PGE2 synthesis was significantly reduced in the duodenum (-73% and -55%) and ileum (-34% and -45%) as compared with the control group. The PGE2 content of the tissue was not significantly changed 24 hours after the single alcohol load and after 1 week of feeding the alcohol-containing diet. However, after 6 and 12 weeks' feeding, the PGE2 content was reduced in both parts of the small intestine. The results suggest a biphasic response to alcohol of PGE2 synthesis in the small intestine. The increased rate of PGE2 synthesis in the initial phase might reflect an adaptive response to the injurious effect of alcohol which cannot be maintained after long-term ingestion of alcohol.