The finding of oligoclonal immunoglobulin (Ig) bands in the cerebrospinal fluid (CSF) is considered a cornerstone in the diagnosis of multiple sclerosis, but can be observed in other diseases as well. In a small subset of patients only a single Ig band, confined to the CSF, is identified. We evaluated the possible diagnostic significance of such a finding. Agarose gels of 6000 CSF samples were re-examined. In 1013 samples (16.8%) there were oligoclonal bands, and in 33 additional samples (0.55%) a single band was found (without a correlating band in the serum). Full data was available for 20 single band patients. Seven patients had clinical definite multiple sclerosis. Of these, 6 had a typically prominent affective disorder and 5 had a relatively malignant course of disease. Seven additional patients had other white matter diseases of the central nervous system (CNS). The remaining patients had inflammatory diseases of peripheral nerves or CNS gray matter and non-inflammatory brain diseases. The frequency of demyelinating diseases of the CNS in patients with a single abnormal Ig band in the CSF was significantly less than in a control group of patients with oligoclonal bands. In conclusion, the finding of a single Ig band confined to the CSF may hint for a disease other than multiple sclerosis, and mark an aggressive course with affective disorder in those who do have multiple sclerosis.