This open, randomized study (ONE: On-demand Nexium Evaluation) compared the two long-term management options with esomeprazole 20 mg--continuous daily or on-demand treatment--in endoscopically uninvestigated patients seeking primary care for symptoms suggestive of gastroesophageal reflux disease (GERD) who demonstrated complete relief of symptoms after four weeks of initial treatment with esomeprazole 40 mg. In total 1904 patients were randomized. During 26 weeks 913 patients received continuous daily therapy with esomeprazole 20 mg, once daily, while 991 patients were treated with esomeprazole 20 mg on-demand. The continuous therapy offered slightly better relief of the symptom heartburn, however esomeprazole 20 mg taken on-demand was associated with lower direct medical costs. Esomeprazole was generally well tolerated.