442 patients suffering from unilateral knee pain were randomized to evaluate the safety and efficacy of 26 weeks of a single-injection of intra-articular non-animal stabilized hyaluronic acid (NASHA) compared to methylprednisolone acetate (MPA). Following 26 weeks of blinded evaluation, patients were offered a second injection with NASHA and were followed for an additional 26 weeks. The evidence presented in this study demonstrated that NASHA gel produced a non-inferior response rate in comparison to MPA. WOMAC pain, physical function, and stiffness evaluations favored NASHA over MPA during the blinded phase from 12 to 26 weeks. Sustained improvements were apparent in WOMAC outcomes irrespective of initial treatment in response to open-labeled extension with NASHA. No serious device-related adverse events were apparent though significantly more cases of arthralgia in the NASHA group were observed during the blinded phase.