Background: Trigeminal neuralgia (TN) is a neurological syndrome characterized by paroxysmal, lightning-like, severe pain in the facial area innervated by the trigeminal nerve. Patients who do not respond well to drug treatment can undergo a nerve block, a traditional conservative treatment. Pulsed radiofrequency (PRF) is a nondestructive pain intervention technique. However, its treatment effectiveness for TN has rarely been reported and remains controversial among scholars. A recent single-center preliminary clinical study showed that high-voltage PRF was significantly effective in the treatment of TN. However, whether high-voltage PRF is a viable pain treatment option for TN patients who are unresponsive to drug treatment must still be confirmed with standardized clinical studies by utilizing conservative nerve block treatment as a control. Objective: To compare the effectiveness and safety of high-voltage PRF and nerve block for primary TN patients who have failed to respond to pharmacological treatment and who are seeking a better non-surgical treatment option. Study Design: Prospective, multicenter, randomized, double-blind, controlled clinical trial. Setting: Three interventional pain management centers in Beijing, China. Methods: The study will include 134 consecutive patients with primary TN who have failed to respond to drug treatment. The patients will be randomly assigned to 2 groups, the nerve block group and the PRF group. The nerve block group will be slowly injected with 1.4 mL of a mixture of dexamethasone and lidocaine after 360 s of sham PRF treatment, and 0.5 mL of normal saline will be administered before the needle is withdrawn. The PRF group will undergo 360 s of 42 degrees C PRF treatment at the highest output voltage that the patients can tolerate, after which the patients will be injected with the same concentration and volume of lidocaine and normal saline that the nerve block group receives. The Barrow Neurological Institute (BNI) pain intensity scale will be used to assess the degree of pain relief before and after the treatment. Results: The effectiveness and safety of high-voltage PRF and nerve block to treat TN will be analyzed to determine significant differences in pain relief and functional improvement. The primary efficacy outcome measure is the response rate at one-year post-operation (BNI I-III/total number of cases* 100%). Secondary efficacy outcome measures include the response rate at postoperative day 1, week 1, week 2, month 1, month 3, month 6 and year 2, the patient satisfaction score (PSS) at various time points, the dosage of antiepileptic drugs (milligrams per day), and information regarding patients with a BNI score of IV or V who switch to other therapies. Limitations: The effects of the waveform, treatment duration, frequency and other parameters of PRF deserve further investigation. Conclusions: This is the first multicenter, double-blind, randomized controlled study to compare the efficacy and safety of PRF and nerve block to treat TN patients who have failed to respond to drug treatment. Moreover, the value of PRF in TN treatment may need to be clinically clarified with evidence-based medical support and other advanced studies.