Background: Hyperhidrosis is a disorder associated with detrimental effects on patients’ quality of life, occupational activities, and social interactions. Objectives: This study compares C-arm guided percutaneous radiofrequency (RF) ablation of the second and third thoracic sympathetic ganglions and local intradermal botulinum toxin type A (BTX-A) injection for the treatment of primary palmar hyperhidrosis. It focuses on clinical effectiveness, patient satisfaction, quality of life, safety, and the time at which repetition of the procedure is needed over one-year follow-up. Study Design: This is a randomized single-blinded trial. Setting: This study took place in a single hospital. Methods: Eighty patients with primary palmar hyperhidrosis were randomly assigned to one of 2 interventions: local intradermal BTX-A injection (n = 40) or C-arm guided percutaneous RF ablation (n = 40). The Dermatology Life Quality Index (DLQI) questionnaire and the Hyperhidrosis Disease Severity Scale (HDSS) were used for assessment at one week, one month, and 2, 6, and 12 months after intervention. The number of patients who required repetition of the procedure later on and the time at which they needed it were recorded, and possible side effects were assessed. Results: HDSS scores in the RF group were statistically significantly lower than in the BTX-A group at one week, one month, and 2, 6, and 12 months of follow-up. DLQI scores in the RF group were statistically significantly lower than in the BTX-A group at 6- and 12-month follow-up, whereas at one week, one month, and 2 months of follow-up, there was no statistically significant difference between both groups. The number of patients who required that the procedure be repeated was statistically significantly lower in the RF group than in the BTX-A group. The time at which patients needed repetition of the procedure in the BTX-A group was about 3 to 7 months after the first intervention. All patients in this group showed an increase in HDSS scores within this one-year followup. In the RF group, however, only one patient complained of increased HDSS scores after 8 months. There was no statistically significant difference in side effects between both groups. Limitations: The first limitation of this study is that results were based on subjective scales. The second is the radiation exposure associated with the technique described. Conclusions: This study supports percutaneous C-arm guided RF ablation of the second and third thoracic sympathetic ganglions and local intradermal BTX-A injection as safe, effective options and rapid lines of treatment of primary palmar hyperhidrosis. However, percutaneous RF ablation proved to be more effective, with longer effectiveness time and better patient satisfaction, compared to local intradermal BTX-A injection.