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The aim of this study was to assess the clinical significance and potential prognostic value of the expression of a panel of surface markers, proliferating, suppressor and oncogenic proteins in diffuse large B-cell lymphomas (DLBCL). Biopsies were collected from 158 patients with DLBCL and analyzed immunohistochemically for p53, p21/WAF1, bcl-2, cyclin-D1, bcl-6, mdr, CD5, CD30, epithelial membrane antigen (EMA), Ki-67 and c-myc positive tumor cells. Among these, 76 young and middle-aged patients (20-65 years) were selected to investigate the relationship between protein expression, clinical features, and survival. Survival analysis showed that advanced stage, high lactic dehydrogenase level, and high International Prognostic Index (IPI) were poor prognostic factors associated with a shorter overall survival (OS) and disease-free survival (DFS) times. A high p53 expression and low bcl-6 expression were associated with a shorter DFS time. The histological variant type, cyclin-D1+ CD5+ DLBCL, positive epithelial membrane antigen (EMA+) CD30− DLBCL, high bcl-2 expression, and low Ki-67 proliferation activity tended to be associated with worse survival, but the correlations were not statistically significant. In the multivariate analysis, the most significant factors were age, followed by IPI and last p53. The expression of p21/WAF1, mdr, and c-myc proteins did not influence OS and DFS. The expression of p53 and bcl-6 proteins may be useful prognostic indicators in DLBCL. Cyclin-D1+ CD5+ or EMA+ CD30− DLBCL tended to predict a worse survival and may probably bear a significant prognostic value worthy of consideration. Overall, clinical factors appeared to be more important than biologic parameters in determining the prognosis of diffuse large B-cell lymphomas.