Background: Recently, genicular nerve block and radiofrequency ablation were introduced to alleviate knee pain in patients with chronic knee osteoarthritis. Both ultrasound- and fluoroscopyguided genicular nerve blocks have been used. However, whether one is superior to the other remains unknown. Objectives: The present study compares the efficacy of ultrasound- vs fluoroscopy-guided genicular nerve blocks. Study Design: This research used a prospective randomized comparison design. Setting: The study took place at a single pain clinic within a tertiary medical center in Seoul, Republic of Korea. Methods: From July 2015 to September 2017, a randomized controlled study was performed to analyze the difference in the efficacy of ultrasound- vs fluoroscopy-guided genicular nerve blocks. The Numeric Rating Scale (NRS-11), Western Ontario and McMaster Universities Arthritis Index (WOMAC), Global Perceived Effect Scales (GPES), and complications were evaluated preprocedure, and 1 and 3 months after genicular nerve block. Results: A total of 80 patients were enrolled and randomly distributed to groups U (ultrasoundguided, n = 40) and F (fluoroscopy-guided, n = 40). Those who were lost to follow-up or had undergone other interventions were excluded, resulting in 31 and 30 patients in groups U and F, respectively. No differences in NRS-11 or WOMAC were observed between the 2 groups at baseline or during the follow-up period. GPES and complication rates were also similar between both groups. Limitations: We were unable to perform double-blind randomization and did not evaluate patients’ baseline emotional states. Conclusions: Pain relief, functional improvement, and safety were similar between groups receiving ultrasound- and fluoroscopy-guided genicular nerve blocks. Therefore, either of the 2 imaging devices may be utilized during a genicular nerve block for chronic knee pain relief. However, considering radiation exposure, ultrasound guidance may be superior to fluoroscopic guidance. The study protocol was approved by our institutional review board (2015-0369), and written informed consent was obtained from all patients. The trial was registered with the Clinical Research Information Service (KCT 0002846). This work was presented in part as D-H Kim’s MS thesis at the University of Ulsan College of Medicine (2018). Key words: Genicular nerve block, ultrasound, fluoroscopy, knee osteoarthritis, Numeric Rating Scale, The Western Ontario and McMaster Universities Osteoarthritis Index