Isolated ileal abnormalities may be detected during routine colonoscopy performed for polyp screening or surveillance. The significance of these abnormalities in asymptomatic patients without a prior diagnosis of inflammatory bowel disease is unknown. A critical clinical issue is whether isolated ileitis in asymptomatic patients is a manifestation of early Crohn disease (CD). We examined clinical, endoscopic, and pathologic data from 29 patients with isolated ileitis and no prior history of inflammatory bowel disease, and no colonic or upper gastrointestinal involvement. Only patients with at least 2 years of follow-up (range: 2.2 to 12.6 y) were included. Fifteen of 29 patients had colonoscopy for gastrointestinal symptoms whereas the remaining 14 were asymptomatic (screening colonoscopy). Seven of 15 (47%) of patients categorized as chronic active ileitis and 3 of 14 (21%) of those classified as focal active ileitis, on blinded histopathologic review, had a clinical diagnosis of CD at last follow-up. One or more features of chronicity were present in 11 of 14 (79%) of asymptomatic ileitis patients but none developed any manifestations of CD on long-term follow-up. In contrast, 8 of 10 (80%) of symptomatic patients with features of chronicity in ileal biopsies progressed to a diagnosis of CD, as did 2 of 5 (40%) symptomatic patients with focal active ileitis. Thus, the presence of symptoms seems to be the best predictor of likelihood of progression to CD in patients with isolated ileitis (P<0.001). Isolated ileitis detected in asymptomatic patients undergoing polyp screening or surveillance does not evolve into CD on follow-up, despite endoscopic and histologic overlap with findings typically seen in CD.