A 3-year-old Asian female presented with fever for 1 week and neck swelling for 1 day. Serology revealed a recent Epstein-Barr virus (EBV) infection. Late on the evening of admission, she developed confusion and would not follow commands. A CT scan showed diffuse cerebral edema and a cerebral flow scan demonstrated no blood flow to the brain. She was declared brain dead and expired on the following day. At autopsy, the brain weighted 1175 grams and grossly showed significant edema. Microscopically, the entire neuraxis revealed extensive leptomeningeal infiltrate of mainly CD8+ T lymphocytes, the majority of which expressed activated markers, HLA-DR and/or CD45RO, and monocytes/macrophages with intermixed numerous apoptotic/karyorrhectic nuclear fragments. These nuclear fragments were considered to be due to apoptosis of the expanded population of CD8+ T lymphocytes. Focal venulitis was noted. EBV-encoded small nuclear RNA in situ hybridization revealed positivity in the occasional lymphocytes. Interestingly, most intraparenchymal as well as leptomeningeal vascular endothelium showed HLA-DR immunoreactivity. This finding has been reported primarily in the acute inflammatory/demyelinating conditions, not in the viral meningitis/meningoencephalitis, and was thought to be related to cytokines due to widespread inflammation in our case. Massive edema secondary to severe EBV-meningitis can be fatal.