The early effects of high toxic doses of vitamin B6 (pyridoxine) on the peripheral sensory neurons were studied in laboratory rats. The animals were treated with 600 mg/kg of pyridoxine hydrochloride by intraperitoneal injection twice daily. Thereafter they were killed by perfusion-fixation at periods ranging from one to 14 days and the tissues were examined by light and electron microscopy. The primary change consisted of the formation of swollen membranous profiles in both the axon hillock and the initial axonal segment of the large dorsal root cytons. This change occurred within 24 hours of exposure, and was followed by an axonal reaction of the nerve cell bodies and by secondary degeneration of their processes. These findings identify the probable target site for pyridoxine toxicity, and establish a simple animal model for studying not only sensory denervation, but also the axonal reaction and secondary degeneration.