Patients with HIV/AIDS have a higher risk of developing aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma (DLBCL). Lymphomas are rather heterogeneous in nature and in a few cases can switch their genetic or immunohistochemical phenotype, transform into other lymphomas or carry more than one malignant clone. In this report, we present the case of a 47-year-old man with HIV infection who was diagnosed with an apparent low-risk, early-stage DLBCL, but became refractory to therapy while undergoing treatment with rituximab-containing chemotherapy. We postulate that the development of his refractory disease occurred in the context of an immunohistochemical switch or the surge of a clone refractory to therapy. This phenomenon was not associated with a superinfection with EBV or HHV-8.