Plasmablastic lymphoma (PBL) is a variant of diffuse large B-cell lymphoma with an aggressive clinical behavior. First described as an Epstein-Barr virus–positive tumor that preferentially occurred in the oral cavity of patients positive for human immunodeficiency virus (HIV) infection, there are increasing reports of this lymphoma in other immunodeficiency states and in immunocompetent elderly patients. The exact incidence in HIV-negative patients is unknown, but PBL accounts for approximately 2.6% of all acquired immune deficiency syndrome–related lymphomas. In the HIV-positive patients, PBL tends to occur in younger patients (39 vs 58 years), in males, and in the oral cavity, as well as to respond better to chemotherapy compared with those diagnosed negative for HIV infection. Histologically, PBLs are diffuse lesions with sheets of tumor cells showing immunoblastic features with variable plasmacytic differentiation. By immunohistochemistry, the lesions are usually negative for CD45 and B-cell markers such as CD20, CD19, CD79a, and Pax-5; are positive for the plasma cell markers such as CD38, VS38c, MUM-1, CD138, BLIMP-1, and XBP-1; and have a high Ki-67 labeling index. Most cases express monoclonal cytoplasmic immunoglobulin G. The lesions are positive for the Epstein-Barr virus in 82% and 46% of the HIV-positive and -negative cases, respectively. Plasmablastic lymphoma may represent a heterogeneous type of lymphoma with a shared immunophenotype but variable degrees of plasmacytic differentiation and different genetic composition resulting in subsets that require different therapy. We present the case of a 33-year-old HIV-positive man diagnosed with an advanced-stage nodal PBL, with an update on the knowledge of this aggressive disease.