Abstract Background Intestinal Ultrasound (IUS) is a non-invasive modality that can assess disease activity, complications, and treatment follow-up in Crohn's disease (CD) patients. IUS is reliable, patient-friendly, and allows frequent monitoring of disease activity. While 3mm bowel wall thickness (BWT) was repeatedly found to correlate with intestinal inflammation, whether this threshold also best predicts clinically relevant future outcomes is still largely unknown. We aim to investigate the role of IUS to predict the risk of therapy failure in biologics-treated CD patients in clinical remission. Methods Our analysis included a retrospective cohort of CD patients in clinical remission (HBI≤4) induces by biologic drugs, who underwent IUS 12 (±2) months after induction. We examined the correlation of IUS activity parameters with future therapy failure (defined as drug discontinuation, dose escalation, new corticosteroid use, CD-related hospitalization, or surgery). Results A total of 57 patients (58% male), with ileal (65%) or ileocolonic (35%) CD, on biological therapy (28% infliximab, 51% adalimumab, 10.5% vedolizumab, 10.5% ustekinumab) were included. Therapy failure occurred in 54.3% (32.2% drug discontinuation, 45.2% dose escalation, 16.2% corticosteroid use and 6.4% hospitalization) during a median follow-up of 12 (IQR 5-22) months after IUS. Of all IUS parameters examined, therapy failure was associated only with increased BWT; BWT > 5mm (hazard ratio (HR) 2.3 [confidence interval (CI) 1.03-5.3], p= 0.041). Interestingly, there was risk plateauing with increased BWT above this cutoff (>5.5 mm (HR 2.2 [CI 1-5.10], p=0.048); >6mm (HR 2.6 [CI 1.17-6.12], p=0.019); >6.5 mm (HR 2.5 [CI 1.08-5.83], p=0.032)) (Figure 1). A BWT cutoff of 3mm could not discriminate patients with future treatment failure. Conclusion Our findings suggest that BWT of > 5 mm during clinical remission can predict subsequent treatment failure in CD patients treated with biologics. Our results support the use of IUS in monitoring CD during remission, and may point to a novel threshold predicting disease reactivation.