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Background Population-based Helicobacter pylori (H.pylori) eradication reduces gastric cancer (GC) risk, yet evidence on its cost-effectiveness is still needed. We conducted an economic evaluation of H.pylori screen-and-treat strategy for GC prevention alongside a large-scale, cluster-randomized, controlled trial.Methods A within-trial economic evaluation was performed from the healthcare system perspective based on the Mass Intervention Trial in Linqu, Shandong Province, China (n=180,284, 2011-2022). H.pylori-positive individuals were randomized to receive anti-H.pylori treatment or symptom alleviation treatment. We examined the incremental mean cost per participant and incremental effect on GC prevention for the cost-effectiveness analysis, and the incremental quality-adjusted life-years (QALYs) and incremental net monetary benefit (INMB) for the cost-utility analysis. Non-parametric bootstrap was used to examine the uncertainty with 5000 replications.Results During 11.8 years’ follow-up, the mean cost per participant was reduced by $11.55 (95% confidence interval (CI): -$4.14, $25.08) for anti- H.pylori treatment, and by $16.89 (95%CI: $3.82, $28.34) for successful eradication, compared with that for symptom alleviation treatment. Anti-H.pylori treatment yielded an estimated reduction of 53.37 (95%CI: 0.18, 99.47) GC cases, and averted 0.0016 QALY loss (95%CI: 0.0001, 0.0031) per participant (INMB= $20.39, 95%CI: $3.68, $37.10). Successful eradication was particularly cost-saving with an estimated reduction of 75.81 (95%CI: 15.96, 123.69) GC cases, and an average gain of 0.0021 QALY (95%CI: 0.0002, 0.0039) per participant (INMB=$28.08, 95%CI: $12.33, $43.83). Besides, H. pylori treatment did not change incremental mean cost, incremental effect or QALYs when other cancers were considered as outcomes (INMB=-$17.90, 95%CI: -$58.63, $22.83). Bootstrapped pairs of costs and QALYs showed that the probability of being cost-saving was 91.88% (4594/5000 replications), and the probability of being cost-effective was 96.48% (4824/5000 replications) for H.pylori-positive individuals receiving anti-H.pylori treatment. Furthermore, H.pylori treatment demonstrated significant cost savings (INMB=$20.86, 95%CI: $7.19, $34.52) for individuals <45 years. Economic benefits remained even when considering trial participants in the screen-and-treat scenario without using symptom alleviation treatment and conducting repeat H. pylori infection test post-treatment, and providing full insurance coverage for H.pylori treatment for individuals aged <45 years.Conclusions Community-based H.pylori screening and treatment was cost-effective for GC prevention and improvement of QALY based on a large-scale intervention trial.