BACKGROUND: Approximately 25% of adults experience heartburn, the cardinal feature of gastro-oesophageal reflux disease (GORD), at least monthly. The evaluation and treatment of patients with suspected GORD is associated with a substantial economic burden. Most patients are treated empirically (without specific diagnostic evaluation). They include a wide range of underlying oesophageal injury. The severity of oesophageal injury can only be established in those who have undergone upper endoscopy. Patients without visible damage to the oesophagus have been referred to as having endoscopy negative reflux disease (ENRD). The pathogenesis of ENRD as well as its response to treatment may differ from GORD with oesophagitis. OBJECTIVES: Summarise, quantify and compare the efficacy of the short-term use of proton pump inhibitors (PPI), H2-receptor antagonists (H2RA) and prokinetics in adults with GORD, treated empirically and in those with endoscopy negative reflux disease (ENRD). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2005), MEDLINE (January 1966 to December 2005), EMBASE (January 1988 to December 2005). SELECTION CRITERIA: Randomised controlled trials focussing on symptomatic outcome after short-term treatment for GORD using proton pump inhibitors, H2-receptor antagonists or prokinetic agents. Studies were included provided that participants could be classified in the empirical treatment group (no endoscopy used in treatment allocation) or in the endoscopy negative reflux disease group (no endoscopic signs of erosive oesophagitis). DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. MAIN RESULTS: Thirty-one trials (9457 participants) were included: fifteen in the empirical treatment group, twelve in the ENRD group and four in both. In empirical treatment of GORD the relative risk (RR) for heartburn remission (the primary efficacy variable) in placebo-controlled trials for PPI was 0.37 (two trials, 95% confidence interval (CI) 0.32 to 0.44), for H2RAs 0.77 (two trials, 95% CI 0.60 to 0.99) and for prokinetics 0.86 (one trial, 95% CI 0.73 to 1.01). In a direct comparison PPIs were more effective than H2RAs (seven trials, RR 0.66, 95% CI 0.60 to 0.73) and prokinetics (two trials, RR 0.53, 95% CI 0.32 to 0.87). In treatment of ENRD, the RR for heartburn remission for PPI versus placebo was 0.69 (seven trials, 95% CI 0.62 to 0.78) and for H2RA versus placebo was 0.84 (two trials, 95% CI 0.74 to 0.95). The RR for PPI versus H2RA was 0.78 (three trials, 95% CI 0.62 to 0.97) and for PPI versus prokinetic 0.72 (one trial, 95% CI 0.56 to 0.92). AUTHORS' CONCLUSIONS: PPIs are more effective than H2RAs in relieving heartburn in patients with GORD who are treated empirically and in those with ENRD, although the magnitude of benefit is greater for those treated empirically.