The aquaporins (AQPs) are water channel proteins that exhibit several properties related to tumor development. However, the expression and clinical significance of AQP5 in colorectal cancer, particularly the correlation with circulating tumor cells (CTCs), has not been elucidated. The aim of the present study was to determine whether or not the expression of AQP5 is a strong prognostic biomarker for colorectal cancer. The results showed that of 45 tumor specimens, 14 (31.1%) had high levels of expression of AQP5, 29 (64.4%) exhibited a moderate (intermediate) level of staining, and 2 (4.4%) had an absence of AQP5 staining. AQP5 was only occasionally detected in para-neoplastic [3/45 (6.67%)] and normal tissues [3/45 (6.67%)]. AQP5 protein overexpression frequently accompanied gene amplification detection with fluorescence in situ hybridization (FISH). Moreover, AQP5 expression in colorectal cancer cells was upregulated compared to normal colon cells. AQP5 overexpression was also associated with TNM stage (P=0.002), lymph node metastasis (P=0.016), and distant metastasis (P=0.000). The relationships between age, gender, histologic grade and tumor size with expression of AQP5 were not significant (P>0.05). A positive correlation between the number of CTCs and AQP5 expression (P<0.05) was demonstrated. In addition, patients who did not express AQP5 had a superior cumulative survival rate compared to patients with AQP5 positivity. AQP5 may be used as a novel biomarker for colorectal cancer aggressiveness and metastasis, but it does not reflect drug resistance.