Many noninfectious diseases can cause signs, symptoms, and cerebrospinal fluid (CSF) abnormalities simulating central nervous system (CNS) infection. Infection usually can be excluded in these cases by the judicious use of serologic tests and CSF stains and cultures. Then, the correct diagnosis is typically suggested by the history and the concomitant presence of clinical and laboratory evidence of disease in other organ systems. Occasionally, particularly when such evidence is absent, the distinction requires meningeal or brain biopsy.