Large B-cell lymphoma (LBCL) carrying MYC rearrangement, alone or together with BCL2 and/or BCL6 translocations, have shown a poor prognosis when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the HIV population. Scanty data are available on the prevalence and prognostic impact of MYC rearrangements in HIV-associated LBCL. We conducted a retrospective study to evaluate the clinical effect of MYC rearrangement in HIV-associated LBCL. We evaluated clinical characteristics, treatment received, and outcome of LBCL in patients with HIV with MYC rearrangement (MYC+) and without MYC rearrangement (MYC-). A total of 155 patients with HIV who had received fluorescence in situ hybridization analysis for MYC were enrolled in 11 European centers: 43 with MYC+ and 112 MYC-. Among patients with MYC, 10 had double-/triple-hit lymphomas, and 33 had isolated MYC rearrangement (single-hit lymphoma). Patients with MYC+ had more frequently advanced stage, >2 extranodal site at presentation, and higher proliferative index. There were no significant differences in overall survival and progression-free survival (PFS) between the 2 groups. However, patients with MYC+ received more frequently intensive chemotherapy (iCT) (44%) than (R)CHOP alone (35%) or infusional treatment (DA-EPOCH-R and R-CDE) (19%). Among patients with MYC+, those who received iCT achieved a better outcome than patients who received nonintensive treatment (complete remission, 84% vs 52%; P = .028; 5-year PFS, 66% vs 36%; P = .021). Our retrospective results suggest that HIV-associated LBCL with MYC+ could be considered for an intensive therapeutic approach whenever possible, whereas (R)CHOP seems to give inferior results in this subset of patients in terms of complete remission and PFS.