Objectives: The involvement of the peripheral nervous system by anti-CV2/CRMP5 paraneoplastic antibodies is typically encountered as a mixed sensorimotor polyneuropathy. We report a fatal case of severe chronic progressive axonal polyradiculoneuropathy in association with this antibody. Methods: Review of the patient's chart, nerve conduction/electromyographic studies, and nerve biopsy. Results: A 51-year-old man presented with a progressive quadriparesis over a 4-month period. Extensive evaluation for potential etiologies was significant only for positive anti-CV2/CRMP5 antibodies without detection of an underlying neoplasm. Despite multiple immunomodulatory therapies, the patient progressed and demonstrated electrodiagnostic evidence for a chronic axonal polyradiculoneuropathy with ongoing denervation. The patient eventually died of respiratory failure. Conclusions: This case adds to the clinical spectrum of the peripheral nervous system involvement in patients with paraneoplastic anti-CV2/CRMP5 antibodies. © 2013 by Lippincott Williams and Wilkins.