Background. Elongation of peripheral nerve by the use of a tissue expander is helpful to repair nerve defects. This study was designed to investigate the effects of some antineoplastic agents on the peripheral nerves under a surgical tissue expansion procedure. Materials and Methods. Twenty-five Wistar rats were used in this study. Following the exposition of the sciatic nerve and placement of two 10/0-nylon sutures in the epineurium 20 mm apart, a tissue expander was then placed under it. Inflation of the expander was immediately accomplished by the separate percutaneous injections of 6, 6, and 8 ml for every 3 min under general anesthesia. The expander was fully deflated at the end of each 3 min The distance between two sutures was measured 1 h later to measure the rate of elongation. Rats were randomly divided into five groups (according to the administered drugs), each consisting of five rats (10 sciatic nerves). Normal saline (1 ml) in the control group (group 1), cyclophosphamide (15 mg/kg) in the group II, cisplatinum (3 mu g/kg) in the group III, mitomycin-C (0.5 mg/kg) in the group IV and 5-fluorouracil (10 mg/kg) in the group V were injected intravenously. Intravenous injections of drugs were performed via the tail vein 30 min before expansion, 48 and 96 h after removal of expander. The incision was reopened on the third and seventh postoperative days, and five sciatic nerves of each group were exposed and then the pinching test was performed to measure regeneration distance. Electro-neurographic changes were recorded. The expanded portion of the sciatic nerve between two sutures was harvested for histological evaluation. Results. There is no significant difference between the elongation rates of all groups (P < 0.05). Histologic evaluation showed that inflammatory changes, vacuolization, intraneural edema, demyelination, axonal changes in the control group, the cisplatinum group and the mitomycin-C group. These changes were significantly decreased in the cyclophosphamide group and the 5-fluorouracil group. In the cyclophosphamide group and the 5-fluorouracil group, the amplitude of compound action potential (CAP) values were significantly higher and the latency was significantly shorter (P > 0.05). Conclusion. We believed that cyclophosphamide and 5-fluorouracil may be helpful in tissue expansion of peripheral nerves, by decreasing the effects of the ischemia-reperfusion injury on the expanded peripheral nerves. (c) 2006 Wiley-Liss, Inc.