Epstein-Barr virus (EBV) has been associated with primary central nervous system lymphoma and other EBV-related malignancies in HIV infected patients, and detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) has been demonstrated to be a good marker of PCNSL. Conversely, EBV has been rarely associated with encephalitis in HIV patients. Here we describe for the first time the case of an HIV-infected, late presenter Caucasian man, diagnosed with a rapidly progressive diffuse encephalitis at presentation. A very high viral load for EBV was detected in CSF by PCR. The patient died 12 days after the onset of encephalitis in spite of supportive, antiviral and antiretroviral therapy. Our experience would suggest that in profoundly immunosuppressed HIV patients EBV may cause severe encephalitis in the absence of lymphoproliferative disorders.