Background <p>Current treatment strategies for vasovagal syncope (VVS) patients recommended by the guidelines are diverse, but effects of these therapies are still unsatisfactory with respective limitations on the indications. Cardioneuroablation (CNA), an innovative and promising therapy, has shown potently effective against syncopal recurrences in numerous observational studies. Recently, a single‐center randomized clinical trial has reported CNA was superior to non‐pharmacologic therapy for VVS patients. Therefore, this study is designed to compare the efficacy of CNA with pharmacologic treatment in a multicenter and randomized fashion.</p> Methods and results <p>The Cardioneuroablation versus Midodrine in Patients with Vasovagal Syncope (CAMPAIGN) study is an international multicenter, prospective, open-label, randomized controlled trial. The recurrent VVS patients with a positive response to tilt testing despite sufficient conventional treatment will be predominantly enrolled at different medical centers in China, Russia, and Turkey. All eligible participants will be randomized in a ratio of 1:1 to treatment with CNA versus midodrine, and followed up for 12&#xa0;months after randomization. Approximately 184 subjects are projected to enroll from April 2023 to December 2024 with follow-up until 2025. The primary endpoint is the recurrence rate of syncope at 12&#xa0;months of follow-up. The secondary endpoints are comprised of quality of life assessed with the Impact of Syncope on Quality of Life, tilt-induced syncope, blood pressure, cardiac deceleration capacity, and heart rate variability.</p> Conclusion <p>A prospective and multicenter clinical trial to compare outcomes of CNA with drug therapy is still lacking. The CAMPAIGN study will provide outcome-based evidence for VVS treatment strategy.</p> Trial registration <p>Clinicaltrials.gov: NCT05803148 (Date: March 9, 2023).</p> Graphical Abstract <p></p>