DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) has a defensive role against alkylating agents associated with increased incidence of malignant tumors. The aim of the current study was to elucidate the significance of immunohistochemical expression of MGMT in squamous cell carcinoma (SCC) of the esophagus, with a special reference to the correlation of smoking. Immunohistostaining of MGMT was performed in the specimens collected from 100 patients with SCC of the esophagus. The relationship between the personal history of smoking and MGMT expression was examined and the value of Brinkman index was compared between patients with and without MGMT expression. Fifty-five SCCs (55.0%) had a positive response to MGMT inununostaining. The proportion of patients who had tumors with MGMT expression among patients with smoking habits was 62.0% (49 out of 79), which was significantly higher than that among patients without smoking habits (28.6%, 6 out of 21; P=0.005). The mean value of Brinkman index in patients who had tumors with MGMT expression (1189+/-604) was significantly higher than that in patients who had tumors without MGMT expression (871+/-656; P=0.020). Our results suggested that MGMT expression in esophageal SCC might be correlated with smoking habits of the patients.