The advent of highly active anti-retroviral therapy (HAART) has reduced both the morbidity and incidence of acquired immunodeficiency syndrome (AIDS)-related central nervous system (CNS) diseases. However, some patients seem to suffer paradoxical clinical deterioration after starting HAART, known as immune reconstitution inflammatory syndrome (IRIS). We report a rare case of probable Mycobacterium avium complex (MAC) infection of the brain in a patient with AIDS who had been treated effectively for probable pulmonary and cerebral MAC infection, with both lesions recurring after significant decreases in plasma human immunodeficiency virus type-1 viral load following initiation of HAART. This case appears to represent the first precise clinicopathological description of severe ventriculo-encephalitis in CNS MAC-related IRIS.