This study describes, for the first time, the neuropathy of zinc pyridinethione (ZPT) toxicity in rats. Although hind-limb weakness has been previously reported as a consequence of dietary ZPT ingestion in rats and rabbits, the cause of the paralysis has been unexplained. Sequential morphologic studies in rats fed a diet containing 166 ppm of ZPT revealed a dying-back neuropathy characterized by the early accumulation of tubulo-vesicular profiles in the motor nerve terminals. Continued exposure resulted in similar abnormalities in the intramuscular nerves and later in the peroneal and posterior tibial nerves and nerve branches to individual muscles. Axonal degeneration and regeneration followed the initial pathologic changes. There was relative sparing of the sensory nerve terminals of the muscle spindles. Central nervous system axons in the long descending tracts of the spinal cord and in the cerebellar vermis showed similar but quantitatively fewer axonal changes compared to the peripheral nerves. The central effects occurred only after prolonged administration of ZPT.