Objective To explore the screening scheme of gastric cancer in large-scale natural population in Wuxi. Methods From December 2016 to December 2019, 105 865 residents of 19 communities (villages) in six streets of Xinwu District, Wuxi were randomly enrolled in this study by random number table. A household epidemiological questionnaire survey was conducted among 50 063 target population subjects (aged 40-69), and then, respondents were divided into four categories, category Ⅰ: HP (-), PG (-); category Ⅱ: HP (+), PG (-); category Ⅲ: HP (+), PG (+); category Ⅳ: HP (-), PG (+)according to the serological Helicobacter pylori (HP) antibodies and pepsinogen (PG) test results. People in category Ⅲ and Ⅳ were all selected into group C and group D respectively, then individuals 3 times of group D were randomly selected from category Ⅰ to assign to group A, and individuals 3 times of group C from category Ⅱwere assigned to group B in the same way. Remaining individuals in category Ⅰ and Ⅱ who had first-degree family history of gastric cancer were also included in group A and group B, respectively. Endoscopic and pathological examination were performed on the above enrolled subjects for high grade intraepithelialneoplasia (HGIN), early gastric cancer and gastric cancer. Results Of the 50 063 target subjects, 31 508 questionnaires were finally collected, with a participation rate of 62.9%. A total of 19 745 people were tested for serology, and the participation rate was 39.4% (19 745/50 063). Serological results showed that there were 11 152 people (56.48%) in category Ⅰ, 8 170 (41.38%) in category Ⅱ, 124 (0.63%) in category Ⅲ, and 299 (1.51%) in category Ⅳ. According to the exclusion criteria and principle of voluntariness, 3 400 individuals were candidates to undergo gastroscopy. Finally, a total of 2 389 people came to the hospital for gastroscopy, 1 263 in group A, 814 in group B, 86 in group C and 226 in group D, with an overall response rate of 70.3% (2 389/3 400),target population participation rate of 4.8% (389/50 063), and the overall population participation rate of 2.3% (2 389/105 865). In the 2 389 cases, there were 32 cases (1.34%) of HGIN and gastric cancer by gastroscopy and biopsy pathology, among which 1 case (3.125%) aged 40-49, 9 (28.125%) aged 50-59, and 22 (68.750%) aged 60-69. Among the 32 cases, 25 cases (78.13%)were pathologically confirmed as having HGIN or early gastric cancer by endoscopic submucosal dissection or surgical operation. By eliminating 810 people (including 3 gastric cancer) without first-degree family history with gastric cancer in group Ⅰ and Ⅱ,and increasing the gastroscopy screening age to 50 years (exluding 214 people aged 40-49, including 1 gastric cancer), the number of people who should undergo gastroscopy could be reduced from 2 389 to 1 365,and 28 cases of HGIN or gastric cancer were still detected, including 22 HGIN or early gastric cancer. Conclusion Gastroscopy after the screening with epidemiological, serological tests, age and first-degree relative with gastric cancer family history is suitable for gastric cancer screening in Wuxi. Based on Chinese national conditions, a new community gastric cancer screening program is recommended in Wuxi considering cost-effectiveness, which includes those over 50 years old, serological PG (+) and first-degree relatives with family history of gastric cancer.