Purpose: Gold standard to predict survival and stratify patients for risk-adapted therapy in diffuse large B-cell lymphoma (DLBCL) is the international prognostic index, although it does not consider the molecular heterogeneity of DLBCL. Deregulation of cyclin E (CCNE) is a strong predictor of poor prognosis in some neoplastic diseases. In tumor cells, it induces chromosomal instability with an increased rate of aneuploidy/polyploidy. Experimental Design: We analyzed in this retrospective study the prognostic value of immunohistochemical CCNE expression on a validated tissue microarray containing 101 de novo DLBCLs and, in 9 cases, the CCNE-induced chromosomal instability as assessed by cytometry. Results: Forty-six of 98 evaluable DLBCLs expressed CCNE in a mean proportion of 20 29% of tumor cells; 38 cases expressed CCNE in >= 20% of tumor cells. CCNE-positive samples were aneuploid compared with near tetraploidy in CCNE-negative cases. Multivariate analysis showed CCNE expression in >= 20% of tumor cells to be an international prognostic index - independent, Adriamycin-based treatment-independent, and BCL2-independent prognostic factor for poor disease-specific survival. CCNE expression in >= 80% of tumor cells was associated with dismal short-term prognosis. CCNE expression in >= 50% of tumor cells emerged as an independent predictive factor for standard CHOP treatment resistance. Conclusions: CCNE expression assessment is easy on paraffin-embedded tissue. The high prognostic value of CCNE expression in DLBCL may be the basis for future prospective trials. In addition, a high CCNE expression hints at the presence of a possible target for individualized cancer therapy.