We report on the design and initial clinical experience with a real-time endoscopic optical coherence tomography (EOCT) imaging system. The EOCT unit includes a high-speed optical coherence tomography interferometer, endoscope-compatible catheter probes, and real-time data capture and display hardware and software. Several technological innovations are introduced that improve EOCT efficiency and performance. In initial clinical studies using the EOCT system, the esophagus, stomach, duodenum, ileum, colon, and rectum of patients with normal endoscopic findings were examined. In these initial investigations, EOCT imaging clearly delineated the substructure of the mucosa and submucosa in several gastrointestinal organs; microscopic structures such as glands, blood vessels, pits, villi, and crypts were also observed.