BACKGROUND: The detection of non-caseating granulomas in histopathological analysis is a key criterion for Crohn's disease (CD) diagnosis. The low frequency of granuloma identification poses a significant challenge to early and accurate diagnosis. This study aims to identify factors affecting granuloma detection rate in CD patients, as well as assess how endoscopic severity and lesion types influence detection, ultimately improving biopsy accuracy and non-caseating granuloma detection rate. METHODS: A retrospective analysis of 308 granuloma-positive CD patients was performed. Age, sex, Montreal classification, endoscopic findings, modified SES-CD scores, and histopathology were collected. Associations between granuloma detection (positive vs. negative) and bowel segment, specimen quantity, and size were evaluated using Chi-square tests. Endoscopic images were graded by modified SES-CD criteria. RESULTS: Granuloma detection was significantly higher in specimens >/= 0.1 cm compared to < 0.1 cm (p < 0.001) and increased with specimen quantity, reaching 68.13 % at N >/= 5 (p < 0.001). The terminal ileum, left colon, and right colon had significantly higher detection rates than the rectum (p < 0.005). Detection rates were higher in the endoscopic mild-to-moderate group than the severe group (p < 0.016) and the normal group (p = 0.001). Ulcerative lesions had significantly higher detection than non-ulcerative lesions (p = 0.001). CONCLUSIONS: The granuloma detection rate correlates with bowel segment, specimen size and quantity, lesion severity, and morphology. Biopsying from regions of mild-to-moderate lesions may enhance granuloma detection.