On November 21, 2012, the U.S. Virgin Islands (USVI) Department of Health documented the first case and death from primary amebic meningoencephalitis (PAM) in the territory. PAM, a rare and almost universally fatal condition, results when Naegleria fowleri, a free-living thermophilic ameba found in warm freshwater, enters the nose and migrates to the brain. The patient was a man aged 47 years whose only reported freshwater exposures were the use of tap water for daily household activities and for ablution, a ritual cleansing that he practiced several times a day in preparation for Islamic prayer. Ablution can include nasal rinsing. On November 16, 2012, the patient had visited the emergency department with a headache; he was treated symptomatically and released. The following day, the patient returned to the emergency department by ambulance with fever, confusion, agitation, and a severe headache, for which he was admitted. Cerebrospinal fluid (CSF) studies were consistent with bacterial meningitis, and antibiotics were started. On November 18, neurologic findings included fixed nonresponsive pupils, no response in the upper or lower extremities, muted plantar responses, and no response to verbal commands. Microscopic examination of the CSF obtained from a second lumbar puncture revealed motile amebic trophozoites. CSF specimens sent to CDC for confirmatory testing were positive for N. fowleri by real-time polymerase chain reaction testing. On the morning of November 21, the patient was pronounced brain dead based on neurologic criteria.