We studied more than 300 cerebrospinal fluid proteins from 21 patients with Creutzfeldt-Jakob disease. We also examined cerebrospinal fluid from 100 normal controls and more than 400 patients with various neurologic disorders other than Creutzfeldt-Jakob disease. Four abnormal proteins that were identified in the patients with Creutzfeldt-Jakob disease were absent in the normal persons. Two of these proteins (Mr [relative molecular mass], 40,000; pl [isoelectric point], 5.7 and Mr 40,000; pl 5.9) were also present in some patients with multiple sclerosis, herpes simplex encephalitis, schizophrenia, Parkinson's disease, or Guillain-Barré or Behçet's syndrome. Two proteins (Mr 26,000; pl 5.2 and Mr 29,000; pl 5.1) were present in all patients with Creutzfeldt-Jakob disease and in 5 of 10 patients with herpes simplex encephalitis, but in none of the other control groups. A subsequent blinded study of these cerebrospinal fluid proteins from patients with Creutzfeldt-Jakob disease, Alzheimer's disease, Huntington's disease, multi-infarct dementia, parkinsonism dementia of Guam, or the specific dementia of the acquired immunodeficiency syndrome resulted in the ability to distinguish all cases of Creutzfeldt-Jakob disease from the other types of dementia. Although the identity and origin of the abnormal spinal fluid proteins are not yet known, these preliminary results suggest that their presence may help in the diagnosis of Creutzfeldt-Jakob disease.