The trefoil factor (TFF) family comprises three thermo-stable and protease-resistant proteins (TFF1, TFF2 and TFF3) and plays an essential role in gastrointestinal mucosa protection and regeneration, and TFFs have recently been found to be involved in the development and progression of various types of cancer. However, the clinical significance of TFFs in colorectal cancer (CRC) patients remains unclear. The present study determined the relationship between TFF expression and clinicopathological findings, as well as long-term outcome in CRC patients. The mRNA expression levels of TFFs were examined in the excised CRC specimens obtained from 154 consecutive CRC patients who underwent surgical resection between 2005 and 2007 at our institution. TFF3 expression was significantly associated with the presence of distant metastasis (p=0.017), although neither TFF1 nor TFF2 expression was associated with the clinicopathological features. Survival rate of the patients with positive TFF3 was significantly worse compared to those with negative TFF3 (p=0.011). A multivariate analysis revealed that the expression of TFF3, lymph node metastasis, and vascular invasion were independent prognostic factors for disease-specific survival. Furthermore, among 134 patients with no clinical findings of metastasis at surgery, the patients with positive TFF3 experienced recurrence within one year more frequently than those with negative TFF3 (p=0.039). In conclusion, TFF3 is not only a useful biomarker for a long-term surgical result in CRC patient, but also may be a risk factor of early recurrence.