In the present study the prognostic impact of new histological and molecular parameters were tested retrospectively in a series of 149 patients with esophageal squamous cell carcinoma (SCC) who underwent potentially curative resection therapy. In addition, the prognostic value of various molecular markers was investigated in a group of 38 patients with locally advanced esophageal SCC treated using combined therapy modalities. In the surgically treated carcinomas, the following morphological parameters proved to be prognostically significant in univariate survival analysis and multivariate survival analysis: pattern of invasion, inflammatory response, and lymph vessel invasion. In contrast, tumor grading according to the criteria of the WHO and tumor cell proliferation did not show significant prognostic impact. Concerning the prognostic influence of molecular parameters, strong expression of the proliferation regulating molecule p21WAF1 and weak expression of the apoptosis regulating molecule Bcl-XL were predictors of poor survival in univariate and multivariate survival analysis. No prognostic impact was shown in relation to the expression of p53 and the apoptosis regulating molecules Bcl-2 and Bax. In the multimodally treated esophageal cancer patients, strong expression of p21WAF1 and accumulation of p53 were predictors of poor survival, whereas expression of Bcl-2, Bax, and Bcl-XL had no prognostic significance. In conclusion, morphological and molecular parameters may provide important prognostic information for esophageal cancer patients.