The study was carried out to investigate the loss of small fibers during entrapment neuropathy and their regeneration after surgical decompression. Entrapment neuropathy was mimicked in a rat model by wrapping the right sciatic nerve of Sprague-Dawley rats with a silastic tube of 1.3 mm inner diameter. A sham operation was performed on the left side. Additional naive rats were used as controls. In the subgroup of rats that received surgical decompression, removal of the tube was performed six months later. Intra-epidermal nerve fiber density (IENFD) was quantified by measuring protein gene product 9.5-immunoreactive epidermal nerve fibers in bilateral hindpaws. The results showed progressive reduction of IENFD after 1, 3, and 6 months of nerve entrapment (e1m, e3m and e6m): naive rats, 20.04+/-2.26 (e1m), 19.39+/-2.38 (e3m), 20.45+/-2.40 (e6m); right side with entrapment, 12.12+/-2.12 (e1m), 6.27+/-1.02 (e3m), 1.83+/-0.48 (e6m); left side after sham procedure, 13.72+/-2.20 (e1m), 8.59+/-1.37 (e3m), 4.56+/-1.07 (e6m) fibers/mm. Small fiber deficit was present both on the side with the entrapment and the contralateral side that had undergone the sham procedure. Increased IENFD was found at 1 and 3 months post-decompression (d1m and d3m), but failed to return to that of the naive rats: naive rats, 20.38+/-2.24 (d1m), 18.94+/-2.24 (d3m); entrapment, 7.00+/-1.14 (d1m), 6.97+/-1.40 (d3m); sham, 6.41+/-1.16 (d1m), 9.92+/-1.64 (d3m) fibers/mm. These findings demonstrate progressive degeneration of small fibers during entrapment neuropathy and partial restoration of innervation after decompression. The results also imply that, in addition to the contralateral side, naive controls are mandatory in the study of small fiber loss in entrapment neuropathy.