Cytomegalovirus encephalitis (CMVE) is frequently diagnosed only at postmortem because its specific clinical features have not been fully identified. We have described the clinical, radiologic, and laboratory features of CMVE in a retrospective review of 14 autopsy-confirmed cases of CMVE and compared them with a control group of demented acquired immunodeficiency syndrome (AIDS) patients without CMVE. CMVE was more common among homosexual men, and a subacute onset was more typical (mean duration of presenting symptoms was 3.5 weeks versus 18 weeks in demented controls). Median survival times were 4.6 weeks for CMVE and 28 weeks for controls. CMVE was accompanied by prominent systemic CMV infection at autopsy, including CMV adrenalitis (92%), CMV pneumonitis (42%), systemic Mycobacterium avium intracellulare (MAI; 58%), and CMV retinitis (58%). Hyponatremia and MAI bacteremia were found in 58% of CMVE cases. Polymerase chain reaction (PCR) of CSF samples identified CMV genome in 33% of CMVE cases. CMVE was associated with periventricular enhancement on CTs and periventricular lesions with meningeal enhancement on MRI scans. CMVE should be particularly suspected in homosexual men presenting with subacute encephalopathy who have had AIDS for more than 1 year and have a history of systemic CMV infection. Other features supporting the diagnosis of CMVE include periventricular lesions, hyponatremia, and identification of CMV genome in CSF by PCR.