Background: Endoscopic healing is an established treatment target for ulcerative colitis (UC). We have recently validated the Milan ultrasound criteria (MUC) to assess endoscopic activity in UC; a MUC score > 6.2 is a valid cut-off to discriminate endoscopic activity (Mayo endoscopic subscore > 1). Objective: The aim of this study was to assess the predictive value of MUC on disease course in a prospective cohort of UC patients. Methods: UC patients regardless of disease activity and current therapy, underwent colonoscopy and bowel ultrasound (US) at baseline in a blinded fashion. Correlations between baseline MUC and Mayo endoscopic subscore were assessed using Spearman's rank correlation. UC-related negative course (defined as the need for corticosteroids, or treatment escalation, or hospitalization, or need for colectomy: a composite outcome) over a median 20 months follow-up, was investigated using the Kaplan-Meier method and Cox regression analysis. Results: 98 UC patients were followed up for a median time of 1.6 years (IQR 0.9¬2.7). Milan ultrasound criteria and Mayo endoscopic subscore significantly correlated at baseline (ρ = 0.653; p < 0.001). 70 patients (71%) had negative disease course during the follow-up period. Milan ultrasound criteria > 6.2 at baseline was statistically significantly associated with negative disease course (HR: 3.87, 95% CI: 2.25-6.64, p < 0.001). Kaplan-Meier analyses drawed a statistically significantly lower cumulative probability of treatment escalation, need of corticosteroids, hospitalization and colectomy, among patients who had MUC ≤ 6.2 at baseline as compared to patients with MUC > 6.2 (p < 0.05 for all outcomes). Conclusion: we have demonstrated for the first time the value of bowel US and an US score in predicting disease course in UC. Milan ultrasound criteria, a validated US-based score, predicts disease course in UC. Milan ultrasound criteria ≤ 6.2 may be the new treatment target to achieve to reduce the risk of worse outcomes.