The aim of the present study was to investigate the expression dynamics of CCL21 and its prognostic significance in human stage III/IV colorectal cancer (CRC). CCL21 expression dynamics were detected with western blotting. The expression of CCL21 in CRC tissue microarrays was examined by immunohistochemistry. The optimal cut-point of CCL21 expression was assessed by the X-tile program. The prognostic significance was analyzed using both Kaplan-Meier curves and Cox regression analysis. Western blot analysis demonstrated that CCL21 expression was comparable in the CRC and normal colorectal tissues. According to the X-tile program, the cut-point for high expression of CCL21 in CRC was determined when the CCL21 expression index was >56.1. Overexpression of CCL21 was significantly correlated with larger tumor diameter, more mucinous carcinoma or signet ring cell carcinoma and poor tumor differentiation. Patients with high expression of CCL21 had a higher overall survival rate in comparison to patients with low expression. In the multivariate Cox regression analysis, CCL21 expression was found to be an independent prognostic biomarker for CRC. ROC curves showed that CCL21 expression could improve the prognostic capability of TNM stage in stage III/IV CRC patients. High expression of CCL21 is an independent and useful biomarker for predicting longer survival of stage III/IV CRC patients.