Abstract Background Mucosal healing has been associated with long-term response to therapy for Crohn disease (CD). However, little is known about the significance of terminal ileum (TI) transmural thickness in predicting clinical outcomes. Methods In this retrospective observational cohort study, we examined the association of an index ultrasonographic assessment of TI thickness during the maintenance phase and the subsequent clinical outcome of CD in a cohort of patients treated with infliximab (IFX). Treatment failure was defined as treatment discontinuation because of lack of efficacy, a need for dose escalation, or surgery. Clinical response was defined as treatment continuation in the absence of any of the aforementioned failure criteria. Results Sixty patients with CD receiving IFX therapy were included in the study. The patients were followed for a median of 16 months (5-24 months) after an index intestinal ultrasound. Thirty-eight patients (63.3%) maintained response to the therapy and 22 patients (36.6%) failed the treatment, with a mean follow up of 10.5 months (6.5-17 months) vs 9.25 months (1-10.25 months), respectively. On univariate analysis, the only variables differing between treatment response and failure were a TI thickness of 2.8 vs 5 mm (P < 0.0001) and an IFX trough level of 6.6 vs 3.9 µg/mL (P = 0.008). On multivariable analysis, only a small bowel thickness of ≥4 mm was associated with the risk of treatment failure (odds ratio, 2.9; 95% CI, 1.49-5.55; P = 0.002). Conclusions Our findings suggest that transmural thickness of ≥4 mm can predict subsequent treatment failure in patients with CD treated using IFX, indicating transmural thickness <4 mm as a potential novel valuable therapeutic target.