Balamuthia mandrillaris is a rare but increasingly recognized cause of amebic encephalitis, yet it remains poorly understood. The condition is almost universally fatal, and due to diagnostic difficulty, most cases are identified postmortem. The authors report a case of Balamuthia amebic encephalitis in a patient with combined variable immunodeficiency in which a rare antemortem diagnosis was made via brain biopsy. Despite broad-spectrum antimicrobial therapy, the outcome was fatal. Such presentations are challenging, and definitive diagnosis may require biopsy in consultation with a skilled neuropathologist.