Background and AimPeriodic endoscopic screening for gastric cancer (GC) is widely performed in East Asia; however, the optimal screening strategy remains unclear. This study aimed to determine the most cost‐effective endoscopic screening strategy for the detection and treatment of GC in a cohort with a low Helicobacter pylori prevalence.MethodsThe following data were retrospectively extracted from participants who received screening endoscopy between April 2019 and March 2023: age, H. pylori infection status, presence of intestinal metaplasia, pathological diagnosis of GC, and the interval between the most recent endoscopies. A Markov state transition model was constructed based on the cohort data. The cost‐effectiveness of 15 strategies with different starting ages (40/50/60 years) and screening intervals (1/2/3/4/5 years) was compared. The net monetary benefit (NMB) and incremental cost‐effectiveness ratio (ICER) of quality‐adjusted life‐years gained by treatment were used as outcomes.ResultsA simulation model was constructed based on the cohort data of 94 137 participants (mean age 54.5 years, males 57.9%; 74.4% H. pylori‐naïve, 94.2% intestinal metaplasia‐negative). The results of the base‐case analysis showed that the screening strategy of 4‐year intervals starting at the age of 40 years had the highest NMB (97 401 578 yen). In both the Monte Carlo simulation and one‐way sensitivity analysis with a varying probability of H. pylori infection status transition, the ICER was superior in the screening strategy every 4 years, starting at age 40 years.ConclusionsOur simulation showed that endoscopic screening at 4‐year intervals starting at the age of 40 years was the most cost‐effective method.