Chronic treatment of rabbits with thalidomide (3-(N-phthalimido) glutarimide) produced progressive decrements in sural nerve conduction velocity (NCV) that were unassociated with qualitative or quantitative morphological changes of nervous tissue. Three groups of eight rabbits received 100 mg/kg/day thalidomide (group I), 200 mg/kg/day supidimide (a related drug) (group II), or a carboxymethylcellulose vehicle (group III) 5 days/week for 40 weeks. At 6 months of treatment, a noninvasive determination of the mean maximum sural NCV for group I was significantly reduced relative to the conduction velocities of groups II and III. Direct measurement of conduction velocity when treatment was terminated confirmed these findings and demonstrated similar conduction deficits in proximal and distal portions of the sural nerve in group I animals. At 6 months, rabbits in group II showed a significant reduction in mean conduction velocity, and, at the termination of treatment, they displayed mean values similar to that of group III and significantly greater than that of group I. Morphological findings were unremarkable in 20 regions of the central nervous system (CNS) and the peripheral nervous system (PNS) known to display changes early in toxic neuropathies. Morphometric estimation of unmyelinated and myelinated fibers in the sural nerve at the heel revealed no between-group differences in axon diameter, fiber diameter, g-ratio (the ratio of inside/outside diameters), or internodal length. In conclusion, chronic treatment with thalidomide produces selected decrements in sural nerve function that have an unknown relationship to the poorly reversible sensory neuropathy reported in humans receiving this drug.