Objective: To investigate the expression of semaphorin 4D (Sema4D) in colorectal carcinoma and its correlation with microvessel density (MVD). Methods: We retrospectively analyzed the clinical and pathological data of 61 patients with colorectal cancer undergoing colorectal surgery from 2014 to 2015 in Yunnan Provincial Tumor Hospital. The expression levels of Sema4D protein in colorectal cancer tissues and 56 cases of normal intestinal mucosal tissue were detected by immunohistochemical SP method. MVD markers were used to count microvessels labeled with CD34. Results: Sema4D was mainly expressed in the cytoplasm and cytoplasm of colorectal carcinoma, and the expression of Sema4D was negative in the cytoplasm of the normal intestinal mucosal tissue. The positive rate of Sema4D expression in cancer tissues (61/61) was significantly higher than that in normal intestinal mucosal tissue (0/56), the difference was statistically significant (χ2=113.027, P<0.001). Sema4D and MVD were analyzed by Spearman correlation coefficient (r=0.333, P=0.009), which had significant positive correlation. T test analysis of MVD expression indicated significant differences between the high and low expression of Sema4D groups (P=0.003). Conclusion: Sema4D is highly expressed in colorectal cancer tissue, and there is a significant correlation with MVD, suggesting that it is potential to be a potential therapeutic target of colorectal cancer.