We have defined a new paraneoplastic immunoglobulin G (IgG) autoantibody specific for CRMP-5, a previously unknown 62-kd neuronal cytoplasmic protein of the collapsin response-mediator family. CRMP-5 is in adult central and peripheral neurons, including synapses, and in small-cell lung carcinomas. Since 1993, our Clinical Neuroimmunology Laboratory has detected CRMP-5-IgG in 121 patients among approximately 68,000 whose sera were submitted for standardized immunofluorescence screening because a subacute neurological presentation was suspected to be paraneoplastic. This makes CRMP-5 autoantibody as frequent as PCA-1 (anti-Yo) autoantibody, second only to ANNA-1 (anti-Hu). Clinical information, obtained for 116 patients, revealed multifocal neurological signs. Most remarkable were the high frequencies of chorea (11%) and cranial neuropathy (17%, including 10% loss of olfaction/taste, 7% optic neuropathy). Other common signs were peripheral neuropathy (47%), autonomic neuropathy (31%), cerebellar ataxia (26%), subacute dementia (25%), and neuromuscular junction disorders (12%). Spinal fluid was inflammatory in 86%, and CRMP-5-IgG in 37% equaled or significantly exceeded serum titers. Lung carcinoma (mostly limited small-cell) was found in 77% of patients; thymoma was in 6%. Half of those remaining had miscellaneous neoplasms; all but two were smokers. Serum IgG in all cases bound to recombinant CRMP-5 (predominantly N-terminal epitopes), but not to human CRMP-2 or CRMP-3.