BACKGROUND: The main objective was to identify risk factors for extent progression in distal ulcerative colitis. The secondary objective was to determine clinical characteristics of disease at the time of progression. METHODS: Data were obtained from a prospective database. Distal colitis was defined as disease limited to rectum and sigmoid colon (n = 178), extensive colitis as involvement of at least the descending colon (n = 179), and colitis with progression when there was a change of category from distal to extensive (n = 63). To study clinical characteristics at the time of progression, a nested case-control study was performed. RESULTS: Compared to distal colitis, colitis with progression was associated to significantly higher prevalence of extraintestinal manifestations (42.9% versus 15.5%) steroid-refractory course (28.0% versus 2.2%), requirement of thiopurines (44.3% versus 17.3%), cyclosporine (25.4% versus 1.9%), infliximab (9.5% versus 1.2%), surgery (20.6% versus 0.6%), and incidence of neoplasia (6.3% versus 0%). However, these differences appeared after disease progression. Regression analysis demonstrated that preexisting independent predictive factors for progression were younger age at diagnosis (hazard ratio [HR] 0.979 95% confidence interval [CI] 0.959-0.999) and presence of sclerosing cholangitis (HR 12.83, 95% CI 1.36-121.10). The nested case-control study showed that at the time of progression the flare was more severe in cases than in matched controls, with significant differences in markers of disease severity, therapeutic requirements, hospitalizations, and surgery. CONCLUSIONS: Patients with distal ulcerative colitis diagnosed at a younger age or with associated sclerosing cholangitis are at higher risk for progression. Disease flare associated with progression follows a severe course with high therapeutic requirements.