BACKGROUND. New biologic agents for Crohn disease (CD) create a need for noninvasive disease markers. DWI may assess bowel inflammation without contrast agents. OBJECTIVE. The purpose of this study was to evaluate ADC values for identifying bowel inflammation and therapeutic response in patients with CD treated with biologic therapy. METHODS. This study entailed post hoc analysis of prospective trial data. Analysis included 89 patients (median age, 37 years; 49 women, 40 men) with CD treated by biologic therapy who underwent MR enterography (MRE) at baseline and 46 weeks after therapy, from March 2013 to April 2021; 43 patients underwent ileocolonoscopy at both time points. Analysis was conducted at the level of small-bowel and colorectal segments (586 segments analyzed). MR index of activity (MaRIA) score and presence of endoscopic ulcers were determined at both time points. One observer measured bowel wall ADC. Diagnostic performance was evaluated. Dichotomous ADC assessments used a threshold of 1301 × 10-6 mm2/s based on initial ROC analysis; dichotomous MaRIA score assessments used a threshold of 11 (moderate to severe inflammation). A second observer repeated ADC measurements in 15 patients. RESULTS. At baseline, ADC had AUC of 0.92, sensitivity of 78.6%, specificity of 91.4%, and accuracy of 88.2% for detecting segments with MaRIA score 11 or greater. At baseline, AUC for detecting endoscopic ulcers was 0.96 for MaRIA score versus 0.87 for ADC (p < .001); sensitivity, specificity, and accuracy were 70.8%, 90.2%, and 85.1% for ADC and 86.2%, 96.2%, and 93.6% for MaRIA score. At follow-up, ADC had AUC of 0.87, sensitivity of 75.4%, specificity of 83.6%, and accuracy of 80.0% for detecting improvement in MaRIA score to less than 11. At follow-up, AUC for detecting endoscopic ulcer healing was 0.94 for MaRIA score versus 0.84 for ADC (p = .01); sensitivity, specificity, and accuracy were 70.7%, 95.8%, and 84.4% for ADC and 90.2%, 100.0%, and 95.6% for MaRIA score. Interobserver agreement for ADC, based on intraclass correlation coefficient, was 0.70 at baseline and 0.65 at follow-up. CONCLUSION. The findings do not support use of ADC rather than MaRIA scores for detecting biologic therapy response. CLINICAL IMPACT. ADC may have an adjunct role in assessing bowel inflammation in CD, but showed limited performance for detecting biologic therapy response.