This report describes the utility and the advantages of endoscopy in diagnosing and following the course of Whipple's disease. Sixteen patients, diagnosed over a period of 22 years, were identified via pathology records and retrospectively reviewed. Five patients were diagnosed before 1980 by means of peroral suction biopsy of the small intestine. The 11 patients diagnosed after 1980 all had upper gastrointestinal endoscopy and endoscopic small intestinal biopsies. Gross endoscopic lesions were observed in 9 of the 11 patients and disappeared in 5 of 6 treated patients at 6 months. These lesions include erosions, yellow plaques, and a pale yellow shaggy mucosa. The latter two lesions are macroscopically suggestive of Whipple's disease. After endoscopic "healing," periodic acid-Schiff-positive macrophages remained present in the endoscopic biopsies for years. The patients were followed for a median period of 4 years and 5 months. All patients were treated with antibiotics (eight tetracycline alone, four tetracycline + streptomycin + penicillin, and four trimethoprim). Five patients (four of the tetracycline alone group, none of the trimethoprim group) relapsed 2 to 11 years after the initial treatment.