OBJECTIVE Currently, few studies have reported the different expression of molecular markers between distal gastric cancer and cardiac cancer. Here, we sought to make an investigation about it by a retrospective analysis. METHODS The expression of 8 proteins, including epidermal growth factor receptor, glutathione S-transferase pi (GST-pi), cyclin D1, Neu/Her-2, C-myc, p53, p27 and p21, were evaluated in 110 cases with cardiac cancer and 101 cases with distal gastric cancer who underwent curative surgery at the Cancer Hospital, Fudan University, in 2005 by immunohistochemistry method. RESULTS The TNM stage, differentiation grade, invasion depth and lymph node metastasis were significantly different between cardiac cancer and distal gastric cancer. p21 (p = 0.034), Neu (p = 0.017), and GST-pi (p = 0.003) were expressed in relatively higher levels in cardiac cancer than in distal gastric cancer. Furthermore, the clinical pathological parameters were significantly correlated with the expression of molecules mentioned above. CONCLUSIONS Different molecular mechanisms may be involved in the tumorigenesis and development of cardiac cancer and distal gastric cancer.