Polystyrene microspheres, the size chosen to plug capillaries and precapillaries, were injected into the arterial supply of rat sciatic nerves. They produced widespread segmental occlusion of capillaries in lower limb nerves. The clinical and pathologic effect was dose-related. One million microspheres produced selective capillary occlusion but no nerve fiber degeneration; approximately 6 million microspheres also produced selective capillary occlusion and associated foot and leg weakness, sensory loss, and fiber degeneration, beginning in a central core of the distal sciatic nerve; 30 million microspheres caused both capillary and arterial occlusion and a greater neuropathologic deficit. From these observations it is inferred that 1) occlusion of isolated precapillaries and capillaries does not produce ischemic fiber degeneration; 2) occlusion of many microvessels results in central fascicular fiber degeneration, indicating that these cores are watershed regions of poor perfusion; and 3) stereotyped pathologic alterations of nerve fibers and Schwann cells are related to dose, anatomic site, and time elapsed since injection.