Epstein-Barr virus (EBV) disease of central nervous system (CNS) in human immunodeficiency virus (HIV) patients is mostly associated with primary CNS lymphoma (PCNSL). In patients who cannot undergo biopsy and have typical clinical and radiographic findings, detection of EBV deoxyribonucleic
acid in CSF may provide enough evidence to start treatment for PCNSL. Here, we described a case of EBV encephalitis presenting with fever, memory, and psycho-motor deficits in a patient with HIV infection and severe immunosuppression who started antiretroviral therapy (ART) one month earlier. Brain magnetic resonance imaging showed periventricular lesions with nodular enhancing pattern and restricted diffusion, and CSF was positive for EBV. Brain biopsy revealed inflammatory lesions and lymphoid infiltrate without signs of malignancy. After three months of ART, patient improved significantly and MRI showed a marked reduction of lesions. Two years later, patient’s condition remains stable. PCNSL is the leading diagnosis in HIV patients with CNS mass lesions and positive CSF for EBV. In the case described, starting treatment for PCNSL could have been considered if the patient could not undergo biopsy, or if there was no improvement under ART. However, EBV encephalitis can be a differential diagnosis in patients with compatible histopathology and clinical course.