Simple SummaryNon-Hodgkin lymphoma (NHL) is one of the most frequent HIV-related neoplasms, and diffuse large B-cell lymphoma (DLBCL) is the most common subtype. In people with HIV (PWH), DLBCL classically presents with aggressive characteristics. As in the general population, HIV-related DLBCL is a heterogeneous disease that includes morphological and molecular subtypes. When combined antiretroviral therapy (cART) became widely available, a strong improvement of the immune function and a better management of infectious complications during lymphoma treatment were observed in PWH with lymphoma. Moreover, the concomitant treatment of cART with chemotherapy was shown to be beneficial. These changes have led to a marked improvement in prognosis for PWH with DLBCL, approaching that of the general population.AbstractDespite the widespread use of combined antiretroviral therapy (cART) and the subsequent decrease in AIDS-defining cancers, HIV-related lymphomas remain a leading cause of morbidity and mortality in people with HIV (PWH). Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype in PWH. This lymphoma is a heterogeneous disease including morphological variants and molecular subtypes according to the cell of origin or the mutation profile. In the pre-cART era, treatment with standard-dose chemotherapy induced high rates of toxicity and outcomes were very poor. The introduction of cART and the incorporation of infection prophylaxis allowed the use of conventional intensive chemotherapy regimens used in the general population, such as R-CHOP or R-EPOCH. The use of cART during chemotherapy treatment was initially controversial due to the potential risk of adverse drug–drug interactions. However, the availability of current cART regimens with less potential to cause drug interactions and evidence that cART improves survival rates in NHL strongly support the use of cART in PWH with DLBCL. Consequently, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the optimal treatment of PWH with NHL.