Purpose To evaluate the safety and clinical outcomes of genicular artery embolization for knee osteoarthritis (OA). Materials and Methods A total of 43 patients suffering from osteoarthritis of the knee (Kellgren and Lawrence grades 2-4) were included in this prospective study. Peri-interventional data including vascular access, embolized target vessels, fluoroscopy time and radiation dose were collected. After 2-, 3- and 12-month pain scores, functional outcomes and adverse events were assessed through a standardized questionnaire. Results All embolizations were performed via a coaxial system consisting of a 4F Cobra catheter and a Microcatheter without the use of an introducer sheath. A mixture of contrast agent (Accupaque, GE, USA) and microspheres (Embosphere, Merit Medical, USA) was injected. At least three genicular branches were embolized per patient with following incidence: inferior lateral genicular artery (77%), superior lateral genicular artery (74%) and descending genicular artery (74%). The mean total volume of permanent embolic agent used was 3.6 +/- 1.3 ml. The average fluoroscopy time was 29 +/- 11 min, and radiation dose was 40.84 +/- 26.21 Gy/cm(2). During the 1-year follow-up, patients pain while walking showed an average reduction of 2.0 +/- 0.5 points on the numeric rating scale (p < 0.0001), without any significant difference between different grades of osteoarthritis. Besides mild transient skin discolorations in four patients, no complications were observed. Conclusion Embolization of multiple genicular artery branches in a single session using microspheres in averaged doses higher than 2 ml total is safe and effective in reducing pain and improving functionality in patients with symptomatic OA, regardless of severity grade.