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Simple Summary: Diffuse large B-cell lymphoma (DLBCL) with MYC/BCL2 double-expression (DE), a recently proposed poor prognostic group, can be easily identified by immunohistochemistry in routine clinical practice. However, clinical outcomes of DE-DLBCL patients vary immensely after R-CHOP immunochemotherapy and prognostic impact of MYC/BCL2-DE was conflicting according to the cell-of-origin, i.e., between germinal center-B-cell (GCB)- and non-GCB-DLBCLs. This implies the heterogeneity within DE-DLBCLs and emphasizes a need for proper risk stratification to select the patients who require more intensive therapy. By analyzing a prospectively immunoprofiled cohort of consecutively diagnosed DLBCL patients, we confirmed the poor prognostic value of MYC/BCL2-DE in DLBCL patients treated with R-CHOP irrespective of the cell-of-origin and international prognostic index. DE-DLBCLs with a concurrent risk factor, especially, elevated serum lactate dehydrogenase (LDH), had the worst survival and DE-DLBCL patients with normal LDH had clinical outcomes similar to those of non-DE-DLBCL patients. Risk stratification of DE-DLBCL based on serum LDH may guide clinical decision-making for DE-DLBCL patients. Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor prognosis and their clinical outcomes after R-CHOP therapy vary immensely. We investigated the prognostic value of DE in aggressive B-cell lymphoma patients (n = 461), including those with DLBCL (n = 417) and high-grade B-cell lymphoma (HGBL; n = 44), in a prospectively immunoprofiled cohort. DE was observed in 27.8% of DLBCLs and 43.2% of HGBLs (p = 0.058). DE-DLBCL patients were older (p = 0.040) and more frequently exhibited elevated serum LDH levels (p = 0.002), higher international prognostic index (IPI; p = 0.042), non-germinal-center B-cell phenotype (p < 0.001), and poor response to therapy (p = 0.042) compared to non-DE-DLBCL patients. In R-CHOP-treated DLBCL patients, DE status predicted poor PFS and OS independently of IPI (p < 0.001 for both). Additionally, in DE-DLBCL patients, older age (>60 years; p = 0.017), involvement of ≥2 extranodal sites (p = 0.021), bone marrow involvement (p = 0.001), high IPI (p = 0.017), CD10 expression (p = 0.006), poor performance status (p = 0.028), and elevated LDH levels (p < 0.001) were significantly associated with poor OS. Notably, DE-DLBCL patients with normal LDH levels exhibited similar PFS and OS to those of patients with non-DE-DLBCL. Our findings suggest that MYC/BCL2 DE predicts poor prognosis in DLBCL. Risk stratification of DE-DLBCL patients based on LDH levels may guide clinical decision-making for DE-DLBCL patients. [ABSTRACT FROM AUTHOR]