CD8 is a membrane glycoprotein of 34 kd on cytotoxic/suppressor T lymphocytes and is an endogenous ligand for MHC class I proteins on target cells. CD8 is released in a soluble form upon T-lymphocyte activation. In multiple sclerosis (MS), T lymphocytes exhibit decreased membrane expression of the CD8 molecule and defective suppressor function. We measured soluble CD8 (sCD8) levels in the CSF of patients with MS, other inflammatory neurologic diseases (INDs), and noninflammatory neurologic diseases (NINDs). sCD8 levels in the CSF of MS and IND patients were elevated compared with NIND patients. Patients with acute infections of the CNS showed the highest absolute values of sCD8, but the amount of sCD8 per CSF white blood cell was greatest in MS and NIND patients. We found no difference in serum sCD8 levels among the groups. In MS, the combination of increased CSF sCD8 levels and sCD8 per cell may reflect CD8 T-lymphocyte activation within the brain or immunodysregulation confined to the CNS.