Pathogen-free granulomatous diseases (PFGD) of the central nervous system (CNS) are a group of disorders with protean clinical and pathological findings. Failure to identify a causative organism leads to considerable diagnostic difficulty. The neuropathology records between 1985 and 1995 were retrospectively reviewed, and the medical records of all patients in whom a diagnosis of PFGD of the CNS was made were retrieved. Patients in whom an infective agent was shown either by culture, special staining techniques, or by immunohistochemical methods were excluded. We identified 11 patients (eight male, three female) who fulfilled the pathological criteria for this condition. Average age at diagnosis was 38.7 years (range, 17 to 78). Neurological symptoms were the presenting feature in nine patients. Neuroimaging findings included hydrocephalus (54.5%), meningeal enhancement (45.5%), and mass lesions (45.5%). Seven patients had antemortem CNS biopsies (brain/meninges [n = 6], spinal [n = 1]), which showed noncaseating granulomas. Eight patients died (mortality rate: 72.7%). Postmortem examination showed granulomatous involvement of the leptomeninges and cerebral parenchyma in all cases with systemic involvement in 50%, chiefly in the form of noncaseating granulomas of the hilar nodes. Six patients fulfilled the clinical, radiological, and pathological diagnostic criteria for neurosarcoidosis. The remaining five patients had an unclassifiable pathogen-free granulomatous disease of the CNS. PFGD of the CNS are associated with a poor prognosis. Although neurosarcoidosis may account for some of the cases, there remains an unclassifiable subgroup that continues to be a diagnostic and management challenge.