Osteoarthritis is characterized by progressive articular cartilage degeneration, changes in subchondral bone and synovial inflammation, leading to pain and disability. Viscosupplementation with hyaluronic acid has been widely investigated due to the viscoelastic properties of this compound to manage pain improving the ability to perform daily activities in patients affected by osteoarthritis. In the present study we investigated the clinical effectiveness of viscosupplementation with a new highly cross-linked hyaluronic acid, Variofill, in patients affected by bilateral knee osteoarthritis in comparison with the widely used Synvisc. A total of 20 patients, aged between 24-74 years and affected by bilateral knee osteoarthritis, participated in this pilot randomized triple-blind clinical study. They received two injections (2 ml each) of Synvisc in their left knee and 2 injections (2 ml each) of Variofill in their right knee spaced 15 days apart. Visual Analogue Scale and Western Ontario McMaster Universities Osteoarthritis Index score were used to evaluate the efficacy of hyaluronic acid injections before and 3 and 6 months after treatment. Both treatment regimens resulted in a significant improvement vs baseline in all endpoints at 3 and 6 months (p less than 0.001). Treatment with Variofill resulted in a high percentage improvement in Visual Analogue Scale pain, Western Ontario McMaster universities Osteoarthritis Index score pain and physical activity, when compared to Synvisc viscosupplementation, at 6 months (p less than 0.05). These results are encouraging for larger clinical trials with Variofill in larger cohorts of patients affected by osteoarthritis of the knee.