Granulomatous amebic encephalitis is an uncommon central nervous system (CNS) infection, usually caused by Acanthamoeba spp., which generally occurs in immunocompromised individuals. Balamuthia mandrillaris is a recently described free-living ameba that occasionally causes fatal CNS disease. The infection might start from a minor, slowly progressive, skin ulceration that can be present for weeks to months before neurologic changes occur. The clinical and histologic presentation is easily confused with many other diseases. Accurate diagnosis requires an awareness of this unusual presentation of amebiasis and identification of the amebic trophozoites in tissue and culture. Special stains are helpful, but immunofluorescence assays or electron microscopy is required to identify the organism as B mandrillaris. We present a fatal case of granulomatous amebic encephalitis that began as a cutaneous infection in an immunocompetent host.