BackgroundSeveral pre-clinical studies have reported the usefulness of artificial intelligence (AI) systems in the diagnosis of esophageal squamous cell carcinoma (ESCC). We conducted this study to evaluate the usefulness of an AI system for real-time diagnosis of ESCC in a clinical setting.MethodsThis study followed a single-center prospective single-arm non-inferiority design. Patients at high risk for ESCC were recruited and real-time diagnosis by the AI system was compared with that of endoscopists for lesions suspected to be ESCC. The primary outcomes were the diagnostic accuracy of the AI system and endoscopists. The secondary outcomes were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and adverse events.ResultsA total of 237 lesions were evaluated. The accuracy, sensitivity, and specificity of the AI system were 80.6%, 68.2%, and 83.4%, respectively. The accuracy, sensitivity, and specificity of endoscopists were 85.7%, 61.4%, and 91.2%, respectively. The difference between the accuracy of the AI system and that of the endoscopists was − 5.1%, and the lower limit of the 90% confidence interval was less than the non-inferiority margin.ConclusionsThe non-inferiority of the AI system in comparison with endoscopists in the real-time diagnosis of ESCC in a clinical setting was not proven.Trial registrationJapan Registry of Clinical Trials (jRCTs052200015, 18/05/2020).