111 patients with knee osteoarthritis were randomized to receive either intra-articular hyaluronic acid (HA) or platelet-rich plasma (PRP) injections. The purpose of this study was to compare clinical and biological measures between treatments. Both groups received three weekly injections. Patient-report outcome measures, clinical examination, and synovial aspirate analysis were assessed over 24 weeks after first injection. Results indicated that patients from both groups experienced significant improvements in all outcomes measured. However, patients in the PRP group displayed significantly greater improvements in International Knee Documentation Committee (IKDC) and pain scores. Interleukin-6 concentrations were found to be significantly higher in the PRP group compared to the HA group at 6 months.