BACKGROUND: It is questionable whether a symptomatic condition with few serious medical consequences requires proton pump inhibitor (PPI) treatment. If effective, a less-potent treatment may be preferable. AIM: To compare an H2-blocker in an effervescent formulation with a PPI in on-demand treatment of endoscopy-negative gastro-oesophageal reflux disease (GERD). METHODS: Included were patients with heartburn and/or acid regurgitation for at least 3 months duration, a negative endoscopy and a positive response to 7 days of lansoprazole 60 mg daily. Following pH-metry, the patients were randomized to receive either ranitidine effervescent tablets 75 mg or lansoprazole capsules 15 mg to a maximum of four per day on-demand. The numbers taken were registered monthly for 6 months. If treatment was unsuccessful (lack of efficacy or side effects), patients were registered as failures. RESULTS: One hundred and three patients were included and 63 were considered for statistical analysis; 32 on lansoprazole and 31 on ranitidine. Seventeen (55%) on ranitidine and four (13%) on lansoprazole failed. The average number of tablets per day was 1.2 in the lansoprazole group and 3.1 in the ranitidine group. CONCLUSIONS: On-demand treatment in patients with endoscopy-negative GERD gives a high success rate with a fairly low dose of PPI. The H2-blocker had significantly less success; nevertheless, almost half were satisfied with the treatment.