99 patients with knee osteoarthritis (OA) were randomized to treatment with either hyaluronic acid (HA) or methylprednisolone acetate (MP) and followed up for 180 days. The purpose of this study was to determine the clinical efficacy and the structural effects of the two intra-articular injections. MP showed lower pain scores compared to HA initially following injection up to 35 days, although the differences between groups at 180 days post-injection were not significant. Second-look arthroscopy in a subset of patients noted improvement in cartilage assessment, particular in the medial tibial compartment and patella compartment, with HA versus MP.