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Some epidemiological surveys have shown an increased incidence of malignancies in patients with multiple Sclerosis (MS). Furthermore, in rare cases central demyelinating disorders like optic neuritis, encephalomyelitis, and myelitis could be of paraneoplastic origin. Antineuronal antibodies are frequently associated with paraneoplastic neurological syndromes (PNS) but are also described in cancer patients without neurological symptoms. In this study, we retrospectively analyzed sera from 247 patients with MS and clinically isolated syndrome (CIS) for the presence of anti-HuD, Yo, Ri, CV2/CRMP5, Ma2, and amphiphysin antibodies using ELISA employing recombinant onconeural antigens. None of the sera revealed high titers of antineuronal antibodies and only two sera from MS patients show weak reactivity, representing in all probability background activity. Furthermore, cancer incidence in our study is low (0.8%%). Our analysis does not support an association between MS and well-characterized paraneoplastic antineuronal antibodies, suggestive of a secondary humoral autoimmune response, underlying latent malignancy, or paraneoplastic origin in our cohort. In reverse, negative screening results in samples of MS patients confirm the high specificity of these antibodies for PNS. [ABSTRACT FROM AUTHOR]