In a carefully controlled multicenter investigation of the effects of oral potassium chloride (KCl) supplements on the gastrointestinal mucosa, 120 healthy men with no endoscopically apparent gastrointestinal lesions were confined to a research ward for 18 days. By random assignment, they were given 60 mEq/day (20 mEq TID) of KCl as either a microencapsulated gelatin capsule, a wax/polymer matrix tablet, or a powder-in-liquid formulation or a placebo capsule for two weeks. All subjects were given glycopyrrolate concomitantly to delay gastric emptying. After treatment was completed, endoscopic examinations of the esophagus, stomach, and duodenum were performed and evaluated by specialists blinded to the particular treatment given. Mild to moderate gastrointestinal irritation, characterized by erythema and edema, was found with similar frequency in all four treatment groups. Two of 30 subjects given the microencapsulated KCl had a single erosion each. Single or multiple erosions were also observed in 14/30 men given the wax/polymer matrix tablet, in 7/30 given the powder, and in 1/30 given placebo. One subject given the wax/polymer matrix tablet had a gastric ulcer. The incidence of gastrointestinal injury with the microencapsulated form was significantly less (P less than 0.01) than that with the wax/polymer matrix tablet and was not significantly different from that seen with either the powder or placebo.