Peripheral sensory-motor neuropathy is one of the most frequent side effects of vincristine (VCR) administration which often limits its usefulness in the treatment of a wide range of neoplastic diseases. Therefore, the purpose of this work is to study VCR neurotoxicity in experimental animals from clinical, electrophysiological and histological points of view in an attempt to highlight some of the pathophysiological mechanisms of this type of neuropathy. Sixty-five rats were used as a control group. Whereas, thirty-one rats were divided into two groups and given VCR in two different regimens, the fixed-dose group (0.2 mg/kg) and the increasing-dose group (0.1 to 0.3 mg/kg, by an increment of 0.05 mg/kg/week). VCR was given intraperitoneally once weekly for five consecutive weeks. In addition to the daily observation for the appearance of any neurological deficit during the period of treatment, electrophysiological examinations of the control and both treated groups were performed. The electrophysiological tests include measurement of nerve conduction velocity (NCV) and action potential (AP) amplitude of sciatic and tail nerves weekly during the period of treatment and fourteen weeks after discontinuation of VCR administration. Histological sections of sciatic nerves were examined at the end of the first, fifth, and the nineteenth weeks of the study (fourteen weeks after discontinuation of treatment). With the progress of the treatment, an increasing number of rats showing signs of neurological deficits were observed. During the first five weeks of this study, electrophysiological testing showed a non-significant difference in the conduction velocities of sciatic and tail nerves between the control and the treated groups, whereas, a significant decrease in the amplitude of the sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) of the tested nerves was recorded. The reduction in the AP amplitude was associated with histological changes characterized by axonal degeneration with relative demyelination. Fourteen weeks after discontinuation of treatment, a significant increment in the SNAP and CMAP amplitudes of both sciatic and tail nerves was noticed. While the CMAP amplitude of the distal segment of the tail showed non significant increment. Less numerous fibers with axonal &/or myelin lesions were found. In conclusion the clinical, electrophysiological, and histological results suggest that VCR induces peripheral sensorimotor neuropathy of axonal type more prominent in the fixed- than the increasing-dose group. The discontinuation of VCR permitted the improvement of the electrophysiological and histological changes. The rat can be used as an animal model for studying VCR neurotoxicity. However, further studies on larger number of animals are required to evaluate the type of nerve fiber involvement and the site of damage.