Factors involved in the development of an insidious polyradiculoneuropathy in association with a procainamide-induced, lupuslike syndrome were explored. A 73-year-old man with this clinical syndrome had sural nerve changes consisting of loss of large myelinated fibers with evidence of remyelination and Schwann cell proliferation. The patient's lymphocytes showed marked incorporation of tritiated thymidine when cultured with either procainamide or extracts of human peripheral nerve myelin, and there was an enhanced response with the combination. We also found that procainamide-treated rats showed acceleration of lymphocyte sensitization to peripheral nerve myelin as judged by the early development of inhibition of macrophage migration and positive skin tests to extracts of peripheral nerve myelin. These studies suggest that procainamide can enhance lymphocyte sensitization to peripheral nerve myelin and may have predisposed this individual to development of a polyradiculoneuropathy.