BACKGROUND Over time, most patients with Crohn's disease (CD) develop strictures or fistulas, resulting in hospitalisations and surgery. Timely therapy with immunomodulators and biologicals may alter this natural history, but carries a significant risk of side-effects. OBJECTIVE To identify factors to predict poor-outcome severe CD at diagnosis, and thus patients who would benefit most from early, aggressive medical therapies. METHODS CD patients (n=101) with uncomplicated non-stricturing, non-penetrating disease at diagnosis, and with follow-up >5 years, were retrospectively analysed using a predefined definition of severe CD (SCD) over the disease course. Clinical, demographic, laboratory and histological factors at diagnosis associated with SCD and poor outcome were evaluated by univariate and multivariate analysis. RESULTS Overall 33.7% of the cohort developed SCD, and on multivariate Cox proportional hazard analysis the presence of granulomas on endoscopic biopsy at diagnosis was independently associated with development of SCD (hazard ratio (HR) 2.3; 95% confidence interval (CI) 1.15 - 4.64; p=0.02). Simple perianal disease was also associated with this outcome (HR 2.49; 95% CI 1.14 - 5.41; p=0.02). The presence of these variables had a specificity of 99% and a positive predictive value of 88%. CONCLUSIONS At diagnosis, factors predictive of SCD in our referral centre were endoscopic biopsy granulomas and perianal disease. Patients with these risk factors should be considered for early, aggressive medical therapy, as benefit will probably outweigh risk. To our knowledge, this is the first study to show that endoscopic biopsy granulomas in patients with uncomplicated (non-stricturing, non-penetrating) CD predict the subsequent development of SCD.