We measured the activity of 2 highly specific autoantibodies (anti-Yo associated with paraneoplastic cerebellar degeneration and anti-Hu associated with paraneoplastic sensory neuronopathy-encephalomyelitis) in simultaneously procured samples of serum and CSF of 18 patients. We also measured the effect of plasma exchange on autoantibody activity in serum and CSF of 6 patients. In 11 patients with paraneoplastic cerebellar degeneration, the CSF/serum ratio of anti-Yo antibody varied between 0.74 and 63, with 8 of 11 patients having ratios substantially greater than 1. In 7 patients with paraneoplastic sensory neuronopathy-encephalomyelitis, the CSF/serum ratio of anti-Hu antibody varied from 0.6 to 44, with 6 of 7 patients having ratios greater than 1. Plasmapheresis reduced the level of the autoantibody in serum without affecting that in the CSF in 5 of 6 patients. These data indicate that autoantibodies in paraneoplastic syndromes are produced in the CNS. This is consistent with the hypothesis of autoimmunity as the pathogenic mechanism. Plasmapheresis failed to effectively remove the antibody from the CNS.