Moderate doses of ethanol were shown to induce a significant rise in prostacyclin (PGI2) concentration in cultures of endothelial cells derived from umbilical veins. Administration of 32 g of ethanol to six volunteers elevated plasma levels of PGI2 in parallel with those of blood alcohol. Although not specific for ethanol, this alcohol induced the largest change in PGI2. Withdrawal of the stimulant alcohol caused prompt reduction of the elevated prostacyclin to baseline values. The activity of ethanol appears to be due to a direct stimulation of cyclooxygenase. The release of [14C]arachidonic acid from prelabeled endothelial cells was decreased by ethanol. PGE2 production was also enhanced by exposure of endothelial cells to ethanol. The physiologic significance of these alcohol-induced changes in PGI2 levels remains to be established.