An autoantibody highly restricted to the nuclei of neurons was found in four patients with subacute sensory neuronopathy and small cell carcinoma of the lung. The antibody was not found in normal subjects or patients with or without cancer who did not have subacute sensory neuronopathy. One- and two-dimensional immunoblotting analysis of nuclear extracts of rat and human brain identified an antibody reactive with a 35-38 kilodalton (kd) basic nucleoprotein. An identical protein lacking the 38 kd peptide was identified in tumor extract of one of the patients. All four patients' serum reacted with the same antigen in the brain and the tumor. In the postmortem study of one of the patients, IgG was found within the neurons of the dorsal root ganglia by direct immunofluorescence. These findings support the hypothesis that the subacute sensory neuronopathy is caused by an antibody that cross-reacts with a tumor cell antigen and a brain nucleoprotein.