The endothelin (ET)-1/endothelin A receptor (ETAR) axis is reportedly involved in tumor cell invasion, survival, and metastasis. However, the role of ETAR in colon cancer metastasis and the underlying mechanisms have not been defined. In the present study, we assessed the role of ETAR in colon cancer metastasis in vitro and in vivo. Overexpression and knockdown of ETAR were respectively performed in SW480 and SW620 human colon cancer cells. Overexpression of ETAR in SW480 cells significantly increased cell survival against cisplatin, cell invasion, and matrix metalloproteinase (MMP)-2 expression, which was strengthened by exogenous ET-1 and abolished by selective ETAR antagonist BQ123 and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Knockdown of ETAR in SW620 cells markedly decreased cell survival against cisplatin, cell invasion, and MMP-2 expression, which was strengthened by BQ123 and LY294002, and partially rescued by exogenous ET-1. In a colon cancer liver metastasis mouse model, while ETAR overexpression promoted colon cancer liver metastases, ETAR knockdown markedly decreased liver metastases. In conclusion, our in vitro data demonstrate that ETAR mediates the promoting effects of ET-1 on colon cancer cell survival, invasion and MMP-2 expression by a PI3K-mediated mechanism. Our in vivo data indicate that ETAR markedly promotes colon cancer liver metastasis. This study provides direct evidence for a critical role of ETAR in colon cancer metastasis, which suggests that ETAR antagonism could benefit patients with metastatic colon cancer. © 2013 Wiley Periodicals, Inc.