Abstract High-grade B-cell lymphoma (HGBL) with translocations involving MYC and BCL2 or BCL6 comprises ∼10% of cases of diffuse large B-cell lymphoma (DLBCL) and carries a poor prognosis. The incidence, prognosis, and optimal therapy for DLBCL harboring extra copies of the genes MYC, BCL2, and BCL6, rather than their genetic translocations, are unknown. In this retrospective, single-center study we identified 144 DLBCL cases including 46 patients with classic HGBL with double-hit or triple-hit chromosomal translocations (DHL), 55 with extra copies of MYC in addition to aberrations (extra copies or translocations) of BCL2 and/or BCL6 but did not meet the criteria for HGBL (EC group), and 43 without any aberrations of MYC, BCL2, or BCL6 (wild type [WT]). Unfavorable baseline characteristics had similar frequency in the EC and WT groups, but were significantly more prevalent in the DHL group. With a median follow-up of 36 months, the 2-year event-free survival (EFS) was similar between the WT and EC groups at 77% (95% confidence interval [CI], 65-90) and 82% (95% CI, 72-93), respectively. In contrast, the 2-year EFS of the DHL group was 63% (95% CI, 51-79). The 2-year overall survival in the WT, EC, and DHL groups was 86% (95% CI, 76-97), 89% (95% CI, 81-98), and 74% (95% CI, 62-88), respectively. Among patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the EC group had outcomes similar to those of the WT group. Our results indicate that patients with DLBCL with extra gene copies of MYC, BCL2, and BCL6 fare differently from those with HGBL and respond well to standard R-CHOP therapy.