Colon cancer is one of the most frequently diagnosed cancer and the third most fatal malignancy worldwide. HOTAIR, a cancer-associated long non-coding RNA (lncRNA), is a powerful biomarker of metastasis and poor prognosis in a diverse group of cancers. Nevertheless, an understanding of how HOTAIR is involved in colon cancer progression is limited. In the present study, we hypothesized that HOTAIR plays a crucial role in colon cancer development. We evaluated the expression of HOTAIR in 120 colon cancer samples, matched adjacent non-tumor mucosa and 32 lymph node metastasis tissues by real-time PCR. Increased HOTAIR expression was significantly correlated with the depth of tumor invasion, lymph node metastasis, organ metastasis, histological differentiation, vascular invasion and advanced tumor stage. Patients with high HOTAIR expression had higher recurrence rates and reduced metastasis-free and overall survival than patients with low HOTAIR expression. Moreover, our findings revealed that HOTAIR had a limited effect on cell proliferation but significantly promoted colon cancer cell migration and invasion in vitro. Depletion of HOTAIR increased the expression of E-cadherin while concomitantly decreasing expression of vimentin and MMP9. Hence, HOTAIR may be another pleiotropic modulator participating in epithelial-mesenchymal transition (EMT). These results indicate that HOTAIR may also be a valuable predictor for colon cancer management; furthermore, this lncRNA may be a potential target for cancer prevention and treatment.