Sera from 23 patients with paraneoplastic disease of the central nervous system (PNS) were examined for the presence of anti-neuronal (anti-Hu, anti-Yo/PCA) and anti-Ri) and systemic auto-antibodies, including antibodies against DNA, centromeres, nRNP, Sm antigen, Scl-70, Ro(SS-A), La(SS-B), mitochondria, thyroid antigens, parietal calls, brush border antigen and rheumatoid factor. As controls, sera from 33 patients with small cell lung cancer, 33 with ovarian cancer and 7 with breast cancer and from 107 aged-matched healthy persons were used. Systemic auto-antibodies were found in 52% of patients with paraneoplastic neurological syndromes compared with only 16% (P = 0.001) in the control group with cancer only and 15% in the group of healthy controls. The relatively high percentage of systemic auto-antibodies in patients with PNS indicates that there is a genetic susceptibility to the development of auto-immune phenomena. This may provide an explanation for the relatively rare occurrence of PNS in patients with cancer.