AIM: To further improve the endoscopic detection of intestinal mucosa alterations due to celiac disease (CD). METHODS: We assessed a hybrid approach based on the integration of expert knowledge into the computer-based classification pipeline. A total of 2835 endoscopic images from the duodenum were recorded in 290 children using the modified immersion technique (MIT). These children underwent routine upper endoscopy for suspected CD or non-celiac upper abdominal symptoms between August 2008 and December 2014. Blinded to the clinical data and biopsy results, three medical experts> visually classified each image as normal mucosa (Marsh-0) or villous atrophy (Marsh-3). The experts decisions were further integrated into state-of-the-art texture recognition systems. Using the biopsy results as the reference standard, the classification accuracies of this hybrid approach were compared to the experts diagnoses in 27 different settings. RESULTS: Compared to the experts diagnoses, in 24 of 27 classification settings (consisting of three imaging modalities, three endoscopists and three classification approaches), the best overall classification accuracies were obtained with the new hybrid approach. In 17 of 24 classification settings, the improvements achieved with the hybrid approach were statistically significant (P < 0.05). Using the hybrid approach classification accuracies between 94% and 100% were obtained. Whereas the improvements are only moderate in the case of the most experienced expert, the results of the less experienced expert could be improved significantly in 17 out of 18 classification settings. Furthermore, the lowest classification accuracy, based on the combination of one database and one specific expert, could be improved from 80% to 95% (P < 0.001). CONCLUSION: The overall classification performance of medical experts, especially less experienced experts, can be boosted significantly by integrating expert knowledge into computer-aided diagnosis systems.