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BACKGROUND & AIMS Helicobacter pylori (H. pylori) infection is considered as the most important risk factor in the pathogenesis of gastric cancer. This study aims to evaluate the long-term effects of H. pylori eradication treatment on the incidence and mortality of gastric cancer among a high-risk population. METHODS This prospective, randomized, placebo-controlled trial was conducted in a high-risk area in southern China in July 1994. A total of 1630 asymptomatic, H. pylori-infected individuals were randomly assigned to receive standard triple therapy for H. pylori eradication (n=817) or placebo (n=813), and were followed up until December 2020. The primary outcome was incidence of gastric cancer. Total and cause-specific mortalities were the secondary outcomes. RESULTS During 26.5 years of follow-up, 21 participants (2.57%) in the treatment arm and 35 (4.31%) in the placebo arm were diagnosed with gastric cancer. Participants receiving H. pylori treatment, compared with their placebo counterparts, had a lower incidence of gastric cancer (hazard ratio [HR]=0.57, 95% confidence interval [CI]: 0.33-0.98). More obvious risk reduction was observed among those without premalignant gastric lesions (HR=0.37, 95%CI: 0.15-0.95) and those without dyspepsia symptoms at baseline (HR=0.44, 95%CI: 0.21-0.94). Further, compared to 32 cases of gastric cancer observed among 527 participants with persistent H. pylori infection in the placebo group, only 16 were identified in 625 subjects with successful eradication in the treatment group (HR=0.46, 95%CI: 0.26-0.83). However, there were no statistically significant differences for any mortality endpoints between two groups. CONCLUSION Eradication of H. pylori might confer a long-term protection against gastric cancer in high-risk populations, especially for infected individuals without precancerous gastric lesions at baseline.