Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) plays an essential role in angiogenesis and development. A previous study showed that the expression of COUP-TFII enhanced invasiveness of human lung carcinoma cells. However, no published data are available concerning the biological and clinical significance of COUP-TFII expression in colorectal cancer. Thus, our objective was to explore the expression of COUP-TFII in colorectal cancer as well as its association with clinicopathological features, and to evaluate the role of COUP-TFII as a prognostic indicator in colorectal cancer. We investigated the presence of COUP-TFII in human colorectal cancer tissues and adjacent normal tissues from 95 primary colorectal cancer patients by immunohistochemistry. The correlation between the expression of COUP-TFII and clinicopathologic features was investigated. The 3-year disease-free survival (DFS) and overall survival (OS) of patients with tumors expressing different levels of COUP-TFII were evaluated by the Kaplan-Meier method. No significant correlation was found between COUP-TFII expression and age at surgery, gender, histopathologic differentiation, vessel invasion, carcinoembryonic antigen (CEA), or nodal involvement. However, survival analysis showed that the COUP-TFII-positive group had a significantly better OS compared to COUP-TFII-negative group (80.4% vs. 57.7%, P=0.0491). Based on our results, COUP-TFII may represent a biomarker for good prognosis in colorectal cancer.