Proton pump inhibitors are the mainstay of medical management in gastroesophageal reflux disease. Although they provide relief from most symptoms, reflux may persist. We hypothesize that omeprazole does not reduce the total amount of gastroesophageal reflux but simply alters its pH characteristics. Six asymptomatic volunteers had combined 24-hour impedance pH monitoring before and after 7 days of omeprazole (20 mg BID). Multichannel intraluminal impedance was used to identify reflux episodes, which were classified as acid (pH < 4), weak acid (pH > 4 but decrease > 1 pH unit) and nonacid (pH > 4 and decrease < 1 pH unit) by pH measurements 5 cm above the lower esophageal sphincter (LES). A gastric pH sensor located 10 cm below the LES was used to verify the action of omeprazole. Impedance detected a total of 116 reflux episodes before and 96 episodes after omeprazole treatment. The median number of reflux episodes (18 versus 16, P = 0.4), median duration of reflux episodes (4.7 versus 3.6 minutes, P = 0.5), and total duration of reflux episodes (27.2 versus 42.4 minutes, P = 0.5) per subject were similar before and after omeprazole. Acid reflux episodes were reduced from 63% before to 2.1% after omeprazole (P < 0.0001), whereas nonacid reflux episodes increased (15% to 76%, P < 0.0001). Weak acid reflux episodes did not change (22.4% to 21.8%, P = 1.0). The proportion of reflux episodes greater than pH 4 increased from 37% to 98% (P < 0.0001). In normal subjects, omeprazole treatment does not affect the number of reflux episodes or their duration; rather it converts acid reflux to less acid reflux, thus exposing esophagus to altered gastric juice. These observations may explain the persistence of symptoms and emergence of mucosal injury white on proton pump inhibitor therapy.