Pheripheral edema was observed in five female patients after taking proton pump inhibitors omeprazole, lansoprazole, or pantoprazole for 7-15 days for peptic acid diseases in recommended standard doses. Edema disappeared two to three days after stopping therapy but reappeared in all five patients after being reexposed to the drugs. In three of the patients drug kinetic investigations were performed and revealed a slow metabolizer status. During dose-finding studies for intravenous proton pump inhibitors omeprazole and pantoprazole, three of six young female volunteers receiving omeprazole and two young female volunteers receiving pantoprazole developed peripheral edema within 8 hr when high doses of the proton pump inhibitors were applied by continuous infusion together with large volumes of fluid. The edema disappeared within 24 hr after stopping the infusion therapy. Serum hormone concentrations in these patients did not change during therapy, neither did the edema factor C1-esterase inhibitor. As a possible mechanism, a competitive inhibition at the receptor site of female hormones involved in water regulation is suspected.