Balamuthia mandrillaris, formerly referred to as a leptomyxid ameba, is a free-living ameba that has recently been identified as a cause of meningoencephalitis. Previously, only two genera, Naegleria and Acanthamoeba, were recognized as causes of central nervous system (CNS) infections in humans. In contrast to Naegleria, Balamuthia causes a subacute-to-chronic infection of the CNS. Distinct from Acanthamoeba, which appears to favor the immunocompromised host, Balamuthia is capable of infecting both healthy and immunosuppressed hosts. Retrospective analyses as well as an accumulation of newly identified cases have demonstrated that this ameba is an increasingly important pathogen to recognize. We report the isolation, histopathologic features, and confirmation by indirect immunofluorescence of B. mandrillaris in a case of fatal amebic meningoencephalitis.