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. Ann Neurol 2001:49:146–154