ObjectivesSince a reliable model for predicting infliximab (IFX) benefits in bio-naïve Crohn’s disease (CD) is still lacking, we constructed a magnetic resonance enterography (MRE)-based model to predict the risk of loss of response to IFX in bio-naïve patients with CD.MethodsThis retrospective multicenter study enrolled 188 bio-naïve patients with CD who underwent MRE before IFX therapy. Therapeutic outcomes were determined based on clinical symptoms and endoscopic findings within 52 weeks. The areas of bowel wall segmentation were decided by two experienced radiologists in consensus. Texture features were extracted using the least absolute shrinkage and selection operator, and a radiomic model was built using multivariate logistic regression. The model performance was validated by receiver operating characteristic, calibration curve, and decision curve analysis.ResultsThe area under the curve of radiomic model was 0.88 (95% confidence interval: 0.82–0.95), and the model provided clinical net benefit in identifying the loss of response to IFX and exhibited remarkable robustness among centers, scanners, and disease characteristics. The high-risk patients defined by the radiomic model were more likely to develop IFX nonresponse than low-risk patients (allp< 0.05).ConclusionsThis novel pretreatment MRE-based model could act as an effective tool for the early estimation of loss of response to IFX in bio-naïve patients with CD.Key Points• Magnetic resonance enterography model guides infliximab therapy in Crohn’s disease.• The model presented significant discrimination and provided net clinical benefit.• Model divided patients into low- and high-risk groups for infliximab failure.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00330-023-09542-y.