Autoantibodies provide serologic markers for subacute cerebellar degeneration in the setting of gynecologic or breast cancer (anti-Purkinje cell cytoplasmic antibodies, PCAb), and for encephalomyeloradiculoneuropathies in the setting of small cell lung carcinoma (type I anti-neuronal nuclear antibodies, ANNA-I). PCAb and ANNA-I are not species-restricted in their specificities. The subject of this report is a systematic immunocytochemical investigation of the distribution and types of cells in the mouse central and peripheral nervous system that bind these IgG autoantibodies. Sera used for the study were from two patients with prototypic PCAb reactivity and two with prototypic ANNA-I reactivity, none of whom had evidence of other autoantibodies, and from four age- and sex-matched healthy control subjects. The patients' clinical features were consistent with the classic syndromes that have been reported with PCAb and ANNA-I, respectively. PCAb bound prominently to the cytoplasm of cerebellar Purkinje cells, and also to other large cytoplasm-rich neurons throughout the central nervous system, to neurons in sensory and sympathetic ganglia and myenteric plexus, and to cells of the adrenal medulla. ANNA-I, on the other hand, bound to virtually all neurons in the central and peripheral nervous system, including sensory and autonomic ganglia, myenteric plexus and cells of the adrenal medulla. An unanticipated finding was that immunoreactivity with ANNA-I was enhanced by fixing tissues briefly with formalin. Astrocyte processes were stained by PCAb and by ANNA-I (but not by the control sera). The cytoplasm of sciatic nerve Schwann cells was stained strikingly by PCAb, but ANNA-I did not bind to Schwann cells. Although it has not yet been determined whether or not PCAb or ANNA-I per se are pathogenic, it is apparent that they represent at least a component of an immune response that is initiated by tumor antigens. The distribution of these tumor-related antigens in the nervous system is consistent with the diversity of neurologic manifestations that can occur in individual patients with the associated paraneoplastic syndromes.