To investigate the efficacy, safety and the duration of treatment effectiveness of intra-articular hyaluronic acid (Artz, Japan) in patients with ankle osteoarthritis (OA).As a prospective clinical trial, 93 patients with unilateral ankle pain for at least 6 months and radiographically classified as Kellgren–Lawrence grade I or II ankle OA were included. After five weekly intra-articular Artz injections, the Ankle Osteoarthritis Scale (AOS), the American Orthopaedic Foot and Ankle Society (AOFAS) ankle/hindfoot score, ankle sagittal range of motion (ROM), patients' global satisfaction, local adverse events and consumption of rescue analgesics were analyzed.Seventy-five patients completed the study. Significant improvement in AOS and AOFAS ankle/hindfoot scores was noted at 1 week, 1 month, 3 months and 6 months post the fifth injection (P<0.001 compared with baseline). The mean reduction of AOS score was 1.9, 2.6, 2.5 and 2.6 at each following visit (P<0.001). The mean AOFAS ankle/hindfoot score improved from 64 points at baseline to 75, 78, 78, and 78 points at 1 week, 1 month, 3 months and 6 months, respectively, post the fifth injection (P<0.001). Ankle sagittal ROM did not improve significantly (P>0.05). The majority of patients reported satisfaction at 1 week (100%), 1 month (100%), 3 months (90.7%) and 6 months (86.7%) follow-up. Local adverse events occurred in 6.7% of patients. Acetaminophen consumption dropped significantly following treatment (P<0.001).Five weekly intra-articular injections of Artz provide pain relief and functional improvements in patients with Kellgren–Lawrence grades I and II ankle OA. The clinical effect was rapid at 1 week and may last for 6 months or more.