Acute, graded, nerve compression was applied to the sciatic nerves of 91 rats in whom an inflatable miniature Plexiglass compression device had been implanted in the thigh. The experiment was designed to study the pathogenesis of lesions in the nerve entrapment syndrome. Under general anesthesia, external pressures of 80 mm of Hg, 30 mm of Hg and 10 mm of Hg were used to compress nerves for 2 hours. Identical compression devices were placed around the contralateral sciatic nerves but remained uninflated so that these nerves could be used as controls. Nerves were excised at intervals of 4 and 24 hours, and at 1, 2, 5, 6, 7, 10, 14, and 28 days, and full thickness transverse sections were made from Araldite blocks. The first pathologic change was nerve edema which was observed at all time points and correlated with the severity of axonal injury. Axonal lesions were predominant in nerves exposed to 80 mm of Hg (7.5 +/- 1.9 nerve fibers per high power microscopic field (HPF)) while nerves compressed at 30 mm of Hg showed fewer damaged axons (2.6 +/- 1.4 per HPF). Demyelination was the predominant lesion in nerves subjected to 30 mm of Hg and was commonly present in nerves around which the compression chamber remained uninflated. Electron microscopy revealed demyelination to be associated with Schwann cell necrosis. The topography of nerve fiber injury was remarkable; subperineurial fibers were often damaged after compression of nerves in which nerve fibers at the core of the fascicle remained unaffected. The findings suggest that local external compression causes ischemia in nerve fibers served by transperineurial vessels, with severe compression causing axonal damage, while lesser degrees of compressive injury are associated with demyelination.