Background: Treatment of Helicobacter pylori (HP) has been shown to reduce the risk ofgastric cancer (GC) development. However, previous studies have focused on patients at high riskof GC. This study aimed to assess the effect of HP treatment on the incidence of GC in the generalpopulation. Materials and Methods: Medical records were obtained from the Common Data Modelconverted sample Cohort of the National Health Insurance Service of Korea (NHIS-CDM). The targetcohort included those who had been prescribed HP treatment and the comparator cohort includedthose who had not. The association between HP treatment and the risk of GC development wasassessed using the Cox proportional hazard model. The incidences of GC according to the period afterHP treatment in different age groups were analyzed using proportional trend tests. Results: Afterlarge-scale 1:4 propensity score matching, 2735 and 5328 individuals were included in the target andcomparator cohorts, respectively. During the median follow-up of 6.5 years, the GC incidence waslower in the HP treatment cohort than in the comparator cohort, but this was statistically insignificant(hazard ratio [HR]: 0.76; 95% confidence interval [CI]: 0.50–1.13; p-value = 0.19). This trend was alsoobserved among the older age (≥65 years, HR: 0.87; 95% CI: 0.44–1.68; p-value = 0.69) and malecohorts (HR: 0.82; 95% CI: 0.51–1.27; p-value = 0.38). Among 58,684 individuals who were treated forHP from the whole NHIS-CDM cohort, the incidence of GC consistently decreased over time andshowed a marked decrease with increasing age (p for trend < 0.05). Conclusions: In all age groups ofthe general population, HP treatment could be recommended to reduce the risk of GC.