Background: The expression of matrix metalloproteinase-21 (MMP-21) has been shown to be elevated in some solid tumor and thought to enhance tumor invasion and metastasis ability. In the present study, we investigated the expression of MMP-21 and its association with prognosis in stage II and III colorectal cancer. Methods: MMP-21 expression was investigated in 286 cases of colorectal cancer by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of MMP-21 expression with clinicopathological characters and overall survival of patients with stage II and III colorectal cancer. Results: MMP-21 expression was significantly higher in colorectal cancer, compared with that in normal epithelial tissue. And it also correlated with tumor invasion, lymph node metastasis, and distant metastasis of colorectal cancer. MMP-21 was also proved to be an independent prognostic factor in patients with stage II as well as stage III colorectal cancer. However, no correlations between MMP-21 expression and patients' age, sex, tumor location, or differentiation status were detected. Conclusion: These results suggested the potential role of MMP-21 in the invasion and metastasis process of human colorectal cancer. It could also be a novel molecular marker to predict prognosis of patients with stage II and stage III colorectal cancer.