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Introduction: HIV-infected patients are affected significantly more frequently by all types of lymphoma, with diffuse large B-cell lymphoma (DLBCL) as the most prevalent histological type. Since the introduction of combination antiretroviral therapy (cART) morbidity and mortality of DLBCL has been markedly reduced, which is primarily interpreted as a result of the drug-mediated immune reconstitution. Case Report: We present a previously healthy, 44-year-old HIV-infected man with DLBCL of the oral cavity, treated with immunochemotherapy and cART. During HIV-directed treatment, despite the successful virologic response, a satisfactory immunological response was not achieved. However, the patient had a 2-year complete remission after first-line treatment of DLBCL. Conclusion: Response to cART strongly predicts outcome in patients with DLBCL. Close monitoring of HIV-directed therapy efficacy, especially as to achievement of successful virologic response, independently associated with prolonged survival, is essential for estimating future DLBCL treatment strategies.