Background: Compliance studies have shown that patients with reflux symptoms generally take their medication only when experiencing these symptoms. Aim: To evaluate the efficacy of on-demand rabeprazole maintenance therapy in patients with non-erosive reflux disease. Methods: This multicentre, randomized, double-blind, placebo-controlled, withdrawal study compared 6 months of on-demand treatment with rabeprazole 10 mg vs. placebo. Adults with a history of reflux symptoms, a negative endoscopy, and ≥3 days of moderate to very severe heartburn in the 7 days before enrolment (N = 535) entered 4 weeks of open-label, acute treatment with rabeprazole 10 mg once daily. Patients with complete symptom relief then entered the on-demand phase. The primary end-point was discontinuation due to lack of heartburn control during the on-demand phase. Results: Eighty-three percent (432 of 523) of patients reported complete symptom relief at the end of the acute phase. During on-demand treatment, rates of discontinuation because of inadequate heartburn control were 20% (28 of 139) for placebo vs. 6% (16 of 279) for rabeprazole (P < 0.00001). Antacid use was twofold higher in the placebo group vs. the rabeprazole group (P = 0.0009). Conclusions: Rabeprazole 10 mg once daily is highly effective in acute symptom relief and as on-demand long-term maintenance therapy in non-erosive reflux disease patients.