The purpose of the study was to examine the response of the endoneurium of the rat sciatic nerve after removal of the epi- and perineurium. For this purpose, segments (4-5 mm long) of the whole epi- and perineurium around the rat sciatic nerve were microsurgically removed (the peel-off area) and the endoneurium was left intact. The post-operative changes were followed up to 5 weeks post-operatively (PO) by histo- and immunohistochemical studies. Additionally, neuromorphometric analyses considering the number of Schwann cells, axons, macrophages and endothelial cells were examined in the peel-off area. The results showed that at the operative area the central part of the endoneurium (65% of the total area of the endoneurium) remained morphologically intact, but the outer part of the endoneurium (35% of the total area) reacted strongly and showed Wallerian type of degeneration. The number of axons and Schwann cells decreased 3 days PO. However, after 2 weeks the number of Schwann cells increased markedly and the highest number was noted 5 weeks PO. A great number of capillaries were observed in the outer part 1 week PO. A rapid invasion of macrophages was noted at the outer part of the endoneurium immediately after the operation. During the regeneration the endoneurial fibroblasts in the peripheral zone started to form minifascicle-like formations, which resulted in a distinct dense outer part of the endoneurium. This dense outer zone was preserved up to 5 weeks PO and participated in the formation of a new perineurium-like structure, but no distinct new perineurium was formed. At the border zone, areas beside the normal epi- and perineurium proliferation of preserved perineurial cells were noted, which fused to the outer part of the dense endoneurium. On focal areas, an attachment of the operated area to the adjoining muscle was observed. This study shows for the first time that despite the microsurgical removal of epi- and perineurium, the inner part of the endoneurium stays intact, but in the outer part of the endoneurium marked reactive changes ensue, probably to protect the injured peripheral nerve.