Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. To identify proteins that are related to the pathogenesis of MS we applied two-dimensional gel electrophoresis of cerebrospinal fluid (CSF) proteins. Proteins were purified by ultrafiltration from 1-ml samples of CSF. Then, four pools were made up from 3–7 samples and the protein precipitated by trichloroacetic acid. About 80 mg of protein was applied per gel from either an MS pool or a control pool. Separation of CSF proteins regularly yielded more that 900 spots. In MS we reproducibly detected 4 spots that were between 5 to 8-fold increased compared to control. MS specific proteins were preferentially found in the pH range between 4–5 and a MW range of 30–70 kDa. In contrast, 9 spots that were preferentially seen in controls were hardly detectable in MS CSF. These 9 spots were reduced to 50–3% of control. The proteins, specific for control CSF, were found in a pH range between 4 and 5 and showed MW between 80–15 kDa. We conclude that CSF from MS patients contains several proteins that occur in increased levels and may be related to the disease or disease progression. On the other hand we observed 9 proteins that were missing or show a decreased level in MS CSF. We suggest that degradative processes eliminate certain proteins from CSF of MS patients. (Supported by BMBF, NBL-3)