T-box2 (TBX2) plays a critical role in embryonic development. Recently, deregulated expression of TBX2 has been implicated in several malignancies. However, the expression and the role of TBX2 in colorectal cancer (CRC) remain unclear. In this study, we found that TBX2 was obviously up-regulated in CRC in comparison with the corresponding normal mucosa at transcriptional and protein level. Up-expression of TBX2 was significantly associated with depth of tumor invasion (P = 0.006), distant metastasis (P = 0.038), advanced AJCC stage (P = 0.008), and relapse (P = 0.003). TBX2 was a significantly prognostic factor for decreased survival and increased disease recurrence independent of tumor stage(II, III stage) and functioned as a biomarker to identify prognosis of patients with CRC (OS: HR 2.154; 95% CI 1.019-4.551; P = 0.044, DFS: HR 2.253; 95% CI 1.109-4.575; P = 0.025). Furthermore, TBX2 could serve as a potential target of cancer drug therapy.