Background: Pulsed radiofrequency (PRF) is a novel nondestructive interventional technique for the treatment of neuropathic pain (NP). However, this intervention is still lack of relevant regulation and the mechanism of action is insofar not clear. Historically, most studies have reported that PRF can relieve reduce hyperalgesia in multiple NP animal models by acting on the dorsal root ganglion. However, a few recent studies have shown that PRF can effectively treat hyperalgesia in pain models by a direct application on injured peripheral nerves. Objectives: To observe changes in pain behavior and the pathology of the sciatic nerve (SN) after applying PRF at the ligation site in a chronic constriction injury (CCI) rat model and to investigate the effect of PRF on the expression of glia cell line-derived neurotrophic factor (GDNF) in nervous tissue. Study Design: A randomized, experimental trial. Setting: Experimental Animal Center, Beijing Tiantan Hospital, Capital Medical University. Methods: Thirty-six adult Sprague-Dawley rats were randomly divided into 3 groups: Sham-Sham (SS), CCI-Sham (CS), and CCI-PRF (CP). The right SNs of the rats in the CS and CP groups were ligated to create a CCI model. For the SS group, the right SN was separated without ligation. On the 14th fourteenth day after surgery, PRF treatment was applied at the ligation site of the SN for the rats in the CP group using a 45 V output voltage at 42 degrees C for 3 minutes. The electrode was placed in rats in the SS and CS groups without electricity applied. The hindpaw withdrawal threshold (HWT) and thermal withdrawal latency (TWL) were measured at various time points before and after the treatments in each group. Optical microscopic scores and electron microscopic observation were given to the right SN ligation sites of the rats in each group 14 days after the treatment. Meanwhile, the GDNF expression levels in the ligation site of the SN and in the L4-L6 spinal cord segments were determined for each group by enzyme-linked immunosorbent assay (ELISA). Results: Fourteen days after PRF treatment, the HWT and TWL values in the CP group were significantly increased compared to those of the CS group (P < 0.01). Under the optical microscope, the axonal number, axonal diameter, and myelin sheath thickness in the CP group were significantly increased compared to those of the CS group 14 days after PRF treatment (P < 0.01). Under the electron microscope, the degeneration at the SN ligation site was significantly improved in the CP group compared to the CS group. The GDNF expression levels at the ligation site of the SN and the L4-L6 spinal segments in the CP and CS groups were increased compared to those of the SS group (P < 0.01). In addition, the GDNF expression in the CP group was significantly higher than that in the CS group (P < 0.01). Limitations: GDNF expression was only measured at day 14 after the treatment rather than at various time points during the experiment. Conclusions: The findings suggest that the application of PRF at the impaired SN relieved reduced the CCI-induced NP by through regulating the upregulation of the GDNF expression in the nervous tissues.