A computer-aided detection (CAD) system for early esophagus carcinoma identification during endoscopy with narrow-band imaging (NBI) was evaluated in a large-scale, prospective, tandem, randomized controlled trial to assess its effectiveness. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2100050654, 2021/09/01). Involving 3400 patients were randomly assigned to either routine (routine-first) or CAD-assisted (CAD-first) NBI endoscopy, followed by the other procedure, with targeted biopsies taken at the end of the second examination. The primary outcome was the diagnosis of 1 or more neoplastic lesion of esophagus during the first examination. The CAD-first group demonstrated a significantly higher neoplastic lesion detection rate (3.12%) compared to the routine-first group (1.59%) with a relative detection ratio of 1.96 (P = 0.0047). Subgroup analysis revealed a higher detection rate in junior endoscopists using CAD-first, while no significant difference was observed for senior endoscopists. The CAD system significantly improved esophageal neoplasm detection, particularly benefiting junior endoscopists.