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Background: Although endoscopic screening for esophageal cancer has been performed in high‐risk areas in China for decades, there is limited and inconsistent evidence regarding the starting age for individuals participating in screening. The aim of this study is to investigate the optimal starting age of esophageal cancer screening. Methods: This study is based on a multicenter prospective cohort consisting 338,017 permanent residents aged 40–69 years in six high‐risk areas of esophageal cancer in China. The participation rate, detection rate, hazard ratios (HRs), cumulative incidence and mortality and number needed to screen (NNS) were calculated in each age group. Screening burden, benefit and risk were compared among screening strategies with different initiation ages to explore the optimal starting age for population‐based screening in high‐risk areas. Results: Individuals aged 50–69 had a higher participation rate, a higher detection rate and improved screening effectiveness than those aged 40–49. The endoscopic screening had no significant effect on reducing the incidence of esophageal cancer in individuals under 55 and mortality in individuals under 45. Increasing the starting age to 50 years reduced the screening demand and NNS by 40% and 55%, and resulted in 12% of detectable positive cases, 16% of preventable incident cases, and 14% of preventable deaths being missed. Conclusions: Postponing the starting age of endoscopic screening to 50 years might yield a more‐favorable balance between screening benefit and burden in high‐ risk areas with limited resources. [ABSTRACT FROM AUTHOR]