To study the differences in expression of several common immunohistochemical markers: epidermal growth factor receptor (EGFR), topoisomerase II (TOPOII), glutathione S-transferase pi (GST-pi), proliferation cell nuclear antigen ( PCNA), Her-2/Neu, P27, P21, and P53, between cardiac carcinoma and carcinoma in antrum of stomach and the correlation thereof with clinicopathological factors. 211 paraffin-embedded tissue samples of gastric cancer were randomly chosen from the patients of cardium and stomach operated in 2005, including 110 cases of cardiac carcinoma and 101 cases of carcinoma in antrum of stomach. Immunohistochemical Envision two step method was used to detect the expression of the above mentioned markers. Compared to the cardiac carcinoma, the carcinoma in antrum of stomach showed higher rate of clinicopathological staging was significantly higher, degree of differentiation lower, invasion deeper, and degree of lymph node metastasis higher (all P < 0.05). The expression rates of P21, Her-2/Neu, and GST-pi of the cardiac carcinoma group were 80.0% (88/110), 30.9% (34/110), and 92.7% (76/82) respectively, all significantly higher than those of the carcinoma in antrum of stomach group [67.0% (65/97), 16.7% (16/96), and 74.5% (41/55) respectively, P = 0.034, 0.017, and 0.003 respectively]. In the cardiac carcinoma, P21 expression was positively correlated with the expression of P27 and EGFR, the P27 expression was positively correlated with the expression of EGFR and TOPOII, and the GST-pi expression was positively correlated with the TOPOII expression (r = 0.255, P = 0.021). In the antrum of stomach carcinoma, GST-pi expression was positively correlated with the expression of EGFR, TOPOII, and Her-2/Neu, however, it was negatively correlated with the expression of PCNA, and the P27 expression was positively correlated with the P53 expression (r = 0.275, P = 0.042). Different molecular mechanisms may lead to the tumorigenesis and development of stomach carcinoma at different sites.