Histopathologic evidence of central nervous system involvement with cytomegalovirus (CMV) has been well recognized in patients infected with human immunodeficiency virus (HIV). However, clinically symptomatic disease has been decidedly less common. In this report, we describe a patient infected with HIV who developed an acute change in neurological status. Gadolinium-enhanced magnetic resonance imaging and analysis of cerebrospinal fluid revealed CMV ventriculitis and meningoencephalitis. Treatment with ganciclovir resulted in radiological improvement of the ventriculitis and negative CMV cultures but little clinical neurological improvement.