Neurophysiologic and neuropathologic changes were studied in rabbit hindlimbs after 2 hours of pneumatic tourniquet application with either 350 mmHg (n = 18) or 1,000 mmHg (n = 6) cuff inflation pressure. The toe spread reflex was decreased in 66% and absent in 33% of limbs 2 days after 350 mmHg compression, and was absent in all limbs after 1,000 mmHg compression. Compound motor action potential amplitudes (CMAPs), recorded from the abductor hallucis muscle, were significantly decreased with sciatic nerve stimulation 1 hour after 350 mmHg compression. CMAPs returned to baseline values one and two days later, however nerve conduction velocity (NCV) was still significantly decreased in the compressed sciatic nerves of these groups. In contrast, complete nerve conduction block, localized beneath the cuff's distal border, was observed two days after 1,000 mmHg compression, and NCV was still significantly decreased distal to the tourniquet zone. Using light and electron microscopy, scattered axonal degeneration, mild myelin damage, and normal nodes of Ranvier were observed two days after 350 mmHg tourniquet compression. Severe fiber damage and nodal obliteration were noted after 1,000 mmHg tourniquet compression. Although nodal invagination is probably not a significant pathogenic mechanism at clinically relevant tourniquet pressures and durations, functional abnormalities were induced by 2 hour, 350 mmHg tourniquet compression. Such changes probably correlate with clinical electromyographic abnormalities and delayed post-operative recovery following 'routine' extremity surgery using pneumatic tourniquets.