Paraneoplastic encephalomyelitis/paraneoplastic sensory neuronopathy (PEM/PSN) associated with small cell lung cancer is characterized by high serum and CSF titers of anti-neuronal (anti-Hu) antibodies and by intrathecal synthesis of anti-Hu IgG. A pathologic role for the anti-Hu antibodies in PEM/PSN is further suggested by reported intraneuronal accumulation of the antibodies in the nervous system of PEM/PSN patients at autopsy. We immunized SJL/J mice, Lewis rats, and Hartley guinea pigs with purified recombinant HuD fusion protein. In spite of high-titer anti-HuD antibodies, neurologic and pathologic examination of the animals was normal. Apparent uptake of purified IgG by neurons in the brain proved to be artifactual.