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Screening a small cell lung cancer cDNA library with serum from a patient with antibody-associated paraneoplastic sensory neuronopathy (Anti-Husyndrome) resulted in the isolation of a cDNA clone encoding the Ro-52 kD antigen. The Ro-52 kD antigen is one of the major antigens recognized by the sera of patients with Sjogren's syndrome and systemic lupus erythematosus. Further investigation revealed that the sera of only a small percentage (4%) of patients with the Hu syndrome reacted with Ro-52 kD antigen. The cross-reactivity may result from a domain of high homology between Ro-52 kD and the HuD antigen. These results emphasize the necessity of using recombinant antigens whenever possible when assaying for specific antibodies.