Mucins play a key role in tumorigenesis. MUC15 is a membrane-bound mucin and the MUC15 messenger RNA (mRNA) has been detected in various organs. However, its role in tumor malignancy is still unclear. This study was to investigate the MUC15 expression in colorectal tumors and the role of MUC15 in colon cancer cells. We found that the mRNA expression of MUC15 was significantly higher in 70.8% (51/72) of colorectal tumors compared with their normal counterparts by real-time reverse transcription-polymerase chain reaction. Immunohistochemistry showed that MUC15 expression was increased in 82.6% (43/52) of colorectal tumors. MUC15 overexpression in HCT116 cells enhanced cell proliferation, cell-extracellular matrix adhesion, colony-forming ability and invasion. Furthermore, these effects were significantly reversed by knockdown of MUC15 with short-hairpin RNA. In nude mice models, MUC15 overexpression significantly (P < 0.01) enhanced tumor growth. In addition, treatment of PD98059 significantly (P < 0.01) inhibited MUC15-enhanced invasion, suggesting that the invasion induced by MUC15 in HCT116 cells was primarily mediated through activation of extracellular signal-regulated kinase 1/2. In conclusion, these results suggest that MUC15 is upregulated in colorectal tumors and its expression enhances the oncogenic potential of colon cancer cells.