BACKGROUND: Platelets play a key role in tumor progression and metastasis. C-type lectin-like receptor 2 (CLEC-2) is the receptor expressed on platelets and the marker of platelet activation. OBJECTIVE: This study aims to determine whether soluble CLEC-2 levels differ between patients with benign colorectal polyps and those with colorectal cancer (CRC). METHODS: We measured plasma soluble CLEC-2 by enzyme-linked immunosorbent assay in 150 patients with colorectal polyps, 150 CRC patients without metastasis, 150 CRC liver metastasis, and 150 control subjects. RESULTS: The CRC patients had higher soluble CLEC-2 levels than patients with colorectal polyps (p< 0.001). Moreover, CRC patients with liver metastases displayed higher CLEC-2 levels than those in CRC patients without metastases (p< 0.001). In the CRC patients, CLEC-2 levels were correlated with lymph node metastasis and advanced stage. In the patients with polyps, there was a significant difference in CLEC-2 levels among patients with hyperplastic polyp, sessile serrated adenoma, and traditional serrated adenoma (p< 0.001). The ROC curve analysis revealed CLEC-2 had an optimal sensitivity of 77.3% and specificity of 94.6% for the screening of CRC, and sensitivity of 71.0% and specificity of 76.7% for the differential diagnosis of colorectal polyps and CRC. CONCLUSIONS: CRC patients have higher CLEC-2 levels than patients with colorectal polyps and healthy controls. Moreover, there is a significant difference in CLEC-2 levels among polyp subtypes. Further research is warranted.