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Aims: Granuloma, mainly composed of macrophages, is a histological feature of Crohn's disease (CD). However, its significance in CD has not been investigated adequately. Our study aims to address this issue by comparing the clinical manifestations and monocyte/macrophage subtypes between granulomatous and non-granulomatous CD. Materials and methods: Demographics, symptoms, endoscopic manifestations, histopathological features, and Montreal classification of patients with and without granulomas were compared. Flow cytometry was used to determine the phagocytosis and subsets of monocytes. ELISA was used to measure the plasma levels of TNF-α, IL-6, IL-1β, IL-10, CCL22, and TGF-β1. Immunohistochemistry was performed to quantify the expression of CD68, CD163 and iNOS. Results: Of the222 CD patients enrolled, granulomas were detected in 90. Compared with non-granulomatous CD patients, those with granulomas had younger age, increased rates of diarrhea and perianal complications, along with higher endoscopic score. Intestinal stenosis and crypt abscess were more frequently observed in granulomatous CD patients. A defective phagocytosis of monocytes was observed in granulomatous CD patients. Meanwhile, higher percentages of intermediate and non-classic monocytes, with a lower percentage of classic monocyte were found in them. Besides, they had higher levels of TGF-β1 and IL-10, a lower level of TNF-α, an increased ratio of CD163+/CD68+cells, and a decreased ratio of iNOS+/CD68+ cells. Conclusions: Granulomatous CD patients exhibited different manifestations compared with their non-granulomatous counterparts. More aggressive therapy may be needed in granulomatous CD patients. Furthermore, the heterogeneity of monocyte/macrophage subsets and altered plasma cytokine may underlie the difference between those two groups. [ABSTRACT FROM AUTHOR]