The melanoma differentiation-associated gene-7 (MDA-7) protein, also known as interleukin-24 (IL-24), is a novel candidate of tumor suppressor that can induce apoptosis experimentally in a variety of human malignant cells. However, there have been few studies about its role in colorectal cancer. We performed immunohistochemical detection of MDA-7/IL-24 in 399 tissue samples from primary colorectal adenocarcinoma patients using a tissue microarray. Western blotting was then done to confirm the immunohistochemical observations. MDA-7/IL-24 immunoreactivity was observed in 116 (29.1%) of the 399 colorectal adenocarcinoma cases. Analysis of the MDA-7/IL-24 expression by Western blotting confirmed the immunohistochemical results. The tumors with a negative MDA-7/IL-24 expression more frequently showed poor differentiation (P=0004), lymph node metastasis (P=0.001), deep invasion (P=0.008) and high stage (P=0.001). A subset of colorectal adenocarcinoma revealed a decreased expression of MDA-7/IL-24, and this was associated with progressive pathologic features. These findings suggest that loss of MDA-7/IL-24 expression may play a role in tumor growth and progression of colorectal adenocarcinomas.