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Objective To investigate the expression and significance of secretory carrier membrane protein 2 (SCAMP2) in colorectal cancer (CRC). Methods Paraffin tissue samples and clinicopathological data were collected from 309 patients with primary CRC who were treated in The Affiliated Hospital of Qingdao University from January 2014 to August 2016, and immunohistochemistry was used to measure the expression level of SCAMP2 in CRC tissue and adjacent tissue. Results SCAMP2 showed a low expression level in CRC tissue and a high expression level in adjacent tissue, and there was a significant difference in the expression level of SCAMP2 between CRC tissue and adjacent tissue (t=5.042,P<0.05). The expression level of SCAMP2 in CRC tissue was associated with tumor size and microsatellite instability (χ2=6.953,4.923,P<0.05). Conclusion The low expression of SCAMP2 in CRC tissue may be closely associated with the development and progression of CRC, and CRC patients with low expression of SCAMP2 tend to have a significant increase in tumor volume, suggesting that SCAMP2 can be used as a potential therapeutic target for CRC.