BackgroundThis protocol is for a multi-centre randomised controlled trial to determine whether the computer-aided system ENDOANGEL-GC improves the detection rates of gastric neoplasms and early gastric cancer (EGC) in routine oesophagogastroduodenoscopy (EGD).MethodsStudy design: Prospective, single-blind, parallel-group, multi-centre randomised controlled trial.Settings: The computer-aided system ENDOANGEL-GC was used to monitor blind spots, detect gastric abnormalities, and identify gastric neoplasms during EGD.Participants: Adults who underwent screening, diagnosis, or surveillance EGD.Randomisation groups:1. Experiment group, EGD examinations with the assistance of the ENDOANGEL-GC;2. Control group, EGD examinations without the assistance of the ENDOANGEL-GC.Randomisation: Block randomisation, stratified by centre.Primary outcomes: Detection rates of gastric neoplasms and EGC.Secondary outcomes: Detection rate of premalignant gastric lesions, biopsy rate, observation time, and number of blind spots on EGD.Blinding: Outcomes are undertaken by blinded assessors.Sample size: Based on the previously published findings and our pilot study, the detection rate of gastric neoplasms in the control group is estimated to be 2.5%, and that of the experimental group is expected to be 4.0%. With a two-sided α level of 0.05 and power of 80%, allowing for a 10% drop-out rate, the sample size is calculated as 4858. The detection rate of EGC in the control group is estimated to be 20%, and that of the experiment group is expected to be 35%. With a two-sidedαlevel of 0.05 and power of 80%, a total of 270 cases of gastric cancer are needed. Assuming the proportion of gastric cancer to be 1% in patients undergoing EGD and allowing for a 10% dropout rate, the sample size is calculated as 30,000. Considering the larger sample size calculated from the two primary endpoints, the required sample size is determined to be 30,000.DiscussionThe results of this trial will help determine the effectiveness of the ENDOANGEL-GC in clinical settings.Trial registrationChiCTR (Chinese Clinical Trial Registry), ChiCTR2100054449, registered 17 December 2021.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13063-023-07346-5.