BACKGROUND & AIMS: Helicobacter 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 had a lower incidence of gastric cancer compared with their placebo counterparts (hazard ratio [HR], 0.57; 95% 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). Furthermore, compared with 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 end points between the 2 groups. CONCLUSIONS: 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.