The subjects in this study consisted of 40 preoperative untreated esophageal squamous cell carcinoma patients. While p53 did not significantly correlate with the clinicopathological factors, E-cadherin significantly correlated with lymphatic invasion, vascular invasion, the depth of invasion, the degree of lymph node metastasis, the histological stage, and the number of lymph node metastases. Epidermal growth factor receptor (EGFR) significantly correlated with age, the depth of invasion, and the number of lymph node metastases. The 5-year cumulative survival rate was 45.7% in the p53-positive cases and 61.9% in the p53-negative cases, with no significant difference, and 87.8% in the E-cadherin-positive cases and 19.1% in the -negative cases, and the difference was significant. The prognosis was significantly poor in EGFR-positive subjects: the 5-year survival rate was 38.6% in EGFR-positive cases and 68% in -negative cases. The 5-year survival rate in E-cadherin-negative, EGFR-positive cases was 0%, while it was 91.7% in the reverse pattern, and this difference was significant. These findings suggest that both E-cadherin and EGFR are important prognostic factors, and a more precise prognosis can thus be obtained by combining them. Such a combined technique may be very useful as an indicator for grading the biological malignancy of esophageal cancer.