OBJECTIVE: The primary objective of this multicenter, randomised, open study was to assess the difference in direct medical costs incurred over a 6-months period with a 20 mg esomeprazole on-demand maintenance strategy, compared to a 20 mg q.d. continuous therapy. Secondary objectives were to assess GERD symptoms and to measure patient satisfaction during the maintenance phase. METHODS: In total, 2884 patients with uninvestigated GERD entered the study and received esomeprazole 40 mg q.d for 4 weeks. At the end of the acute treatment phase 93% patients were symptom free (complete resolution of heartburn or not more than 1 day with mild heartburn during the last 7 days prior to the visit), and were randomised to receive either continuous or on-demand treatment (esomeprazole 20 mg) during a 6-month maintenance phase (1315 and 1325 patients respectively). Analyses were performed on an intention to treat basis. Direct costs include study, OTC and other GERD medication, unscheduled visits and GERD tests. RESULTS: The proportion of patients heartburn free at 6 months was significantly higher (p <0.001) in the continuous treatment with esomeprazole 20 mg (86.1%) than in the on demand group (78.0%). Patient's satisfaction reached 94% after the 4 weeks acute treatment and remained 92% in the maintenance phase, similar in both groups. Both treatment arms were well tolerated. Mean daily direct costs were significantly lower ( P <0.001) in the on demand group (€0.96 +/-0.54 SD) than in the esomeprazole 20mg q.d. arm (€1.39 +/-0.31 SD). The proportion of patients taking GERD- related drugs was similar in the two groups (8.0% vs 7.3%, p = 0.6). CONCLUSIONS: Continuous or on-demand treatment in patients with uninvestigated GERD offer effective and safe symptom control with a high patient satisfaction. On-demand treatment allows significant reduction in medical costs. Choice of treatment should be considered on patient basis.