Enprostil, a synthetic analogue of prostaglandin E2, has been shown to protect the human gastroduodenal mucosa from aspirin injury. This study was designed to determine if enprostil protected against alcohol damage. A double-blind, randomized, crossover study was performed on eight healthy adult men. After an overnight fast, a gastroscope was inserted and the antral mucosa was sprayed with a 10-mL test solution containing either enprostil (70 μg) or its vehicle (control). After 15 minutes, mucosal injury was scored (0-5), and the mucosa was sprayed with 100 mL 80% ethanol. Mucosal injury was scored after a further 15, 20, 25, and 30 minutes. The entire experiment was recorded on video film, which a second endoscopist used to score the damage independently. The two experiments were seperated by an interval of 1 week. There was close agreement between the two endoscopists (r = 0.9385), and their scores were averaged. Using Friedman's two-way analysis of variance, a highly significant (P < 0.00004) increase in injury was demonstrated following enprostil pretreatment. The Wilcoxin signed rank test showed the differences to be significant (P < 0.05) at every time point. We conclude that enprostil, rather than protecting the human antral mucosa from alcohol injury, appears to potentiate this injury and may itself be damaging in therapeutic concentrations. This unexpected result cannot yet be explained but demands caution in the clinical use of enprostil. © 1990.