Eighty-nine patients who had been treated by ileal resection for Crohn's disease between 1979 and 1984 were included in a prospective cohort follow up to study the natural course of early postoperative lesions. Recurrent lesions were observed endoscopically in the neoterminal ileum within 1 year of surgery in 73% of the patients, although only 20% of the patients had symptoms. Three years after surgery, the endoscopic recurrence rate had increased to 85% and symptomatic recurrence occurred in 34%. The ultimate course of the disease was best predicted by the severity of the early postoperative lesions, as observed at ileoscopy. Clinical parameters that influenced outcome were preoperative disease activity, the indication for surgery, and the number of surgical resections. When patients were stratified for preoperative disease activity, the severity of lesions found at endoscopy remained a strong predictive factor for symptomatic recurrence. In 22 other patients submitted to "curative" ileal resection and ileocolonic anastomosis, the segment to be used as neoterminal ileum was carefully examined during surgery, and two large biopsies were taken before making the anastomosis. An ileoscopy was performed 6 months after surgery. Although all patients had a macroscopically normal neoterminal ileum and 19 had entirely normal biopsies at the time of surgery, 21 patients were found at ileoscopy to have developed ileitis involving a 15-cm segment (range, 4-30 cm), and 20 had unequivocal microscopic lesions on biopsies. These studies suggest that early lesions in the neoterminal ileum after Crohn's resection do not originate from microscopic inflammation present in this bowel segment at the time of surgery. The early postoperative lesions in the neoterminal ileum seem to be a suitable model to study the pathogenesis of Crohn's disease and also to evaluate new therapeutic modalities, either to prevent development of these early lesions or to treat progressive recurrence.