OBJECTIVES: The optimal approach for management of patients with dyspepsia has not been determined. The aim of this study was to compare the efficacy of three strategies for management of dyspepsia: empirical antisecretory therapy, testing for Helicobacter pylori (H. pylori), or a combination of the two. METHODS: Cluster-randomized trial in general practices. Initial treatment with proton pump inhibitor (PPI) was performed in 222 patients, H. pylori test-and-eradicate in 250 patients, and PPI followed by H. pylori-testing if symptoms improved in 250 patients. Symptoms, quality of life, patient satisfaction, and use of resources were recorded during a 1-yr follow-up. RESULTS: The prevalence of H. pylori infection was 24%. We found no difference among the three strategies (p = 0.16) in terms of the proportion of days without dyspeptic symptoms. After 1 yr gastrointestinal symptom scores and quality-of-life scores had improved significantly and equally in the three groups (p < 0.001), but no statistically significant differences were found among the groups. The mean use of endoscopies per patient after 1 yr was higher in the PPI group (0.36 [95% CI 0.30-0.43]) than in the test-and-eradicate group (0.28 [95% CI 0.23-0.34]) and the combination group (0.22 [95% CI 0.17-0.27]), p = 0.02. H. pylori-positive patients given eradication therapy had more days without dyspeptic symptoms (p < 0.001), used less antisecretory therapy (p < 0.01), and were more satisfied (p < 0.001) than H. pylori-negative patients. CONCLUSION: The strategies based on H. pylori test enjoyed similar symptom resolution, but reduced endoscopic workload and lower 1-yr total costs compared with empirical antisecretory therapy.