Smad signaling pathway plays an important role in tumorigenesis and progression in cancer (Halder, S.K., Rachakonda, G., Deane, N.G., Datta, P.K., 2008. Smad7 induces hepatic metastasis in colorectal cancer. Br. J. Cancer 99, 957-965). The protein level of Smad is associated with growth, inhibition, and metastasis in different cancers. It is unclear if the differentiation, metastasis and apoptosis are reduced by Smad expression pattern in gastric cancer. To determine the effect of Smad on gastric cancer cells, we investigated the relationship of Smad4/Smad7 expression, and differentiation, metastasis, and apoptosis in different gastric cancer. The results show that Smad4 expression in the gastric cancer tissue was dramatically lower than that in the peritumoral tissue. A lower expression of Samd4 was significantly lower in the poorly differentiated tissue than that in the well and middle differentiated tissues (P<0.01). In contrast, Smad7 expression in gastric cancer tissues was significantly higher than that in the peritumoral tissue. Smad7 was overexpressed in poorly differentiated tissue, also higher than those in the middle, and well differentiated tissues (P<0.05). The Smad4 or Smad7 expression obviously related with the lymphatic metastasis in gastric cancer. There were 45 cases with lymphatic metastasis in all 78 patients. Smad4 expression in the cases with lymphatic metastasis was lower than the cases without metastasis (P<0.01), whereas Smad7 expression in the cases with lymphatic metastasis was much higher than the case without metastasis (P<0.01). To better understand the mechanisms involved in tumorigenesis of gastric cancer, we established SGC7901 gastric cancer cell lines transduced with Smad4 or Smad7 plasmid DNA. Apoptosis and survival of cancer cells was induced after Smad4 and Smad7 transduction. This effect is concentration and time dependent. Thus, this study provides a mechanism by which a balance between Smad4 and Smad7 in human gastric cancer is critical for differentiation, metastasis, and apoptosis of tumor cells.