Enprostil, a synthetic prostaglandin E2 analog, has been shown to decrease gastric acid secretion and plasma gastrin levels during short-term treatment. However, effects of prolonged treatment with enprostil on these parameters in humans are unknown. We have studied the effects of 35 micrograms enprostil twice daily on 24-hour intragastric pH, basal gastrin, and meal-stimulated gastrin release in 10 healthy volunteers. Enprostil, 35 micrograms, was ingested twice daily for 4 weeks. Subjects were studied on day 0 (preentry) and days 1 and 29, when enprostil was taken 30 minutes before the first and third standard test meals at 9 AM and 5 PM. Enprostil significantly increased 24-hour median pH (p < 0.02) on day 1 but not on day 29. Enprostil had no significant effect on basal gastrin levels compared with placebo. However, on day 1, but not on day 29, postprandial gastrin levels were significantly lower compared with preentry (p < 0.05). On day 29 post-prandial gastrin levels after the second standard test meal were significantly higher compared with preentry data (p < 0.05). In conclusion, 35 micrograms enprostil twice daily reduced gastric acidity and serum gastrin levels on the first day of treatment, but this effect attenuated and even transiently reversed during a 4-week treatment period.