We describe, to our knowledge, the first reported case of Schistosoma mekongi infection with brain involvement. S. mekongi is a distinct species most closely related to Schistosoma japonicum that is endemic in a defined area of the Mekong River in Laos and Cambodia and characteristically associated with hepatosplenic disease. The patient had an excellent response to praziquantel therapy but required repeated courses of corticosteroid therapy to suppress recrudescent neurological symptoms.