Objective: To evaluate the efficacy and feasibility of screening procedure for upper gastrointestinal cancer in both high-risk and non-high-risk areas in China.Setting: Seven cities/counties, representing three economical-geographical regions(Eastern, Central and Western) in China, were selected as screening centers: three in high-risk areas and four in non-high-risk areas.Participants: Villages/communities in these seven centers regarded as clusters were randomly assigned to either intervention group(screening by endoscopic examination) or control group(with normal community care) in a 1:1ratio stratified by each center. Eligible participants are local residents aged 40–69 years in the selected villages/communities with no history of cancer or endoscopic examination in the latest 3 years who are mentally and physically competent. Those who are not willing to take endoscopic examination or are unwilling to sign the consent form are excluded from the study. Totally 140,000 participants will be enrolled.Interventions: In high-risk areas of upper gastrointestinal cancer, all subjects in screening group will be screened by endoscopy. In non-high-risk areas, 30% of the subjects in screening group, identified through a survey,will be screened by endoscopy.Primary and secondary outcome measures: The primary outcome is the mortality caused by upper gastrointestinal cancer. The secondary outcomes include detection rate, incidence rate, survival rate, and clinical stage distribution. Additional data on quality of life and cost-effectiveness will also be collected to answer important questions regarding screening effects.Conclusions: Screening strategy evaluated in those areas with positive findings may be promoted nationally and applied to the majority of Chinese people. On the other hand, negative findings will provide scientific evidence for abandoning a test and shifting resources elsewhere.Trial registration: The study has been registered with the Protocol Registration System in Chinese Clinical Trial Registry. Objective: To evaluate the efficacy and feasibility of screening procedures for upper gastrointestinal cancer in both high-risk and non-high-risk areas in China. Letting: Seven cities / counties, representing three economical-geographical regions (Eastern, Central and Western) in China, were selected as screening centers: three in high-risk areas and four in non-high-risk areas. Participants: Villages / communities in these seven centers regarded as clusters were randomly assigned to either intervention group (screening by endoscopic examination) or control group (with normal community care) in a 1: 1ratio stratified by each center. Eligible participants are local residents aged 40-69 years in the selected villages / communities with no history of cancer or endoscopic examination in the latest 3 years who are mentally and physically competent. Those who are not willing to take endoscopic examination or are unwilling to sign the consent form are excluded from the study. Totally 140,000 participant s will be enrolled. Interventions: In high-risk areas of upper gastrointestinal cancer, all subjects in screening group will be screened by endoscopy. In non-high-risk areas, 30% of the subjects in screening group, identified through a survey, Primary outcome is the mortality caused by upper gastrointestinal cancer. The secondary outcomes include detection rate, incidence rate, survival rate, and clinical stage distribution. Additional data on quality of life and cost -effectiveness will also be collected to answer important questions regarding screening effects.Conclusions: Screening strategy as in certain areas with positive findings may be promoted nationally and applied to the majority of Chinese people. On the other hand, negative findings will provide scientific evidence for abandoning a test and shifting resources elsewhere. Trial registration: The study has been registered with the Protocol Registration System in Chinese Clinical Trial Registry.