Hylan G-F 20, which is derived from hyaluronan, is a highly purified, elastoviscous fluid with rheologic properties similar to those of synovial fluid in the knee joints of healthy young persons. The efficacy and safety of viscosupplementation with hylan G-F 20 were evaluated in a multicenter, double-masked clinical study in patients with chronic idiopathic osteoarthritis (OA) of the knee of 1 to 30 years' duration. Three intra-articular injections of 2 mL hylan G-F 20 were administered 1 week apart to 57 knees. The control group (60 knees) received 2 mL of physiologic buffered saline solution at the same intervals. Patients were predominantly female (65%), with a mean age of 62 years and mean weight of 76 kg. Using a visual analogue scale, patients assessed the following clinical variables: pain during weight-bearing, pain at rest during the night, reduction of pain during the most painful movement of the knee, and treatment success. Evaluators also assessed patients' loss of activity while performing difficult daily tasks and treatment success. There was dramatic early improvement in all six variables with hylan G-F 20 beginning after the first injection; the improvement continued through the study end points. The differences between hylan G-F 20 and saline treatment were statistically significant for all outcome measures. In the hylan G-F 20 group, 39% to 56% of patients were free or nearly free of weight-bearing pain 10 to 24 weeks after the last injection. Treatment with saline was less effective, with fewer than 13% of patients free or nearly free of weight-bearing pain. Use of rescue therapy was significantly greater in the saline group than in the hylan G-F 20 group. No adverse events were observed in the injected joint after hylan G-F 20 treatment. These results demonstrate that hylan G-F 20 is effective and well tolerated in the management of chronic idiopathic OA.