372 patients with Kellgren-Lawrence grade I-III knee osteoarthritis (OA) were randomized to either four intra-articular injections of high-molecular-weight (HMW) hyaluronic acid (HA), three intra-articular injections of HMW HA and one control arthrocentesis, or four sessions of control arthrocentesis. The primary outcome was the percentage of patients demonstrating a minimum 20% relative reduction from baseline in WOMAC pain score. Follow-up was conducted at 8, 12, 16, and 22 weeks after the first treatment session. All groups demonstrated a significant improvement from baseline in pain measures, and there were no significant between-group differences in the degree of pain reduction throughout follow-up. The four-injection HA group demonstrated a significantly higher rate of patients demonstrating a minimum reduction of 20% in WOMAC pain at 8 weeks, but not at any subsequent follow-up time points. At no time point did the three-injection HA group demonstrate a significantly higher rate than the control group for the primary outcome. Patients with Kellgren-Lawrence grade I knee OA severity were removed from the primary outcome analysis that was presented, and left group sizes below the a priori sample size calculation.