BCL2 and MYC are oncogenes commonly deregulated in lymphomas. Concurrent BCL2 and MYC translocations (BCL2⁺/MYC⁺) were identified in 54 samples by karyotype and/or fluorescence in situ hybridization with the aim of correlating clinical and cytogenetic characteristics to overall survival. BCL2⁺/MYC⁺ lymphomas were diagnosed as B-cell lymphoma unclassifiable (BCLU; n = 36) with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL); DLBCL (n = 17), or follicular lymphoma (n = 1). Despite the presence of a t(14;18), 5 cases were BCL2 protein–negative. Nonimmunoglobulin gene/MYC (non-IG/MYC) translocations occurred in 24 of 54 cases (44%) and were highly associated with DLBCL morphology (P < .001). Over a median follow-up of 5.3 years, 6 patients remained in remission and 32 died within 6 months of the MYC⁺ rearrangement, irrespective of whether MYC⁺ occurred at diagnosis (31 of 54) or transformation (23 of 54; P = .53). A non-IG/MYC translocation partner, absent BCL2 protein expression and treatment with rituximab-based chemotherapy, were associated with a more favorable outcome, but a low International Prognostic Index score and DLBCL morphology were independent predictors of overall survival. A comprehensive cytogenetic analysis of BCL2 and MYC status on all aggressive lymphomas may identify a group of high-risk patients who may benefit from chemotherapeutic regimens that include rituximab and/or BCL2-targeted therapy.