The main objective of this study is to determine the safety and efficacy of the intra-articular injections (IA) of Sodium hyaluronate and methylprednisolone in the treatment of osteoarthritis (OA) of knee. The study was carried out in the orthopedic department of a multispeciality hospital for a period of 6 months from November 2013 to April 2014. Total number of 46 patients with OA of knee were categorized into two treatment groups, sodium hyaluronate (Group A, n= 26) and methylprednisolone (Group B, n= 20). Group A and B patients received sodium hyaluronate IA injection once a week for continuous 3 weeks and methylprednisolone IA injection once in 6 months. Pain score was assessed based on VAS (Visual Analogue Scale) and the recordings were done at baseline (1st visit), review 1 (2 weeks after IA injection), review 2 (4 weeks after IA injection) and review 3 (8 weeks after IA injection). ADRs for both the treatment groups were monitored and assessed. Sodium hyaluronate significantly reduced the VAS mean pain score with baseline-6.27, review 1–5.00, review 2–3.96 and review 3–3.15 for Group A patients and baseline-7.79, review 1–6.15, review 2–5.15 and review 3–5.68 for Group B patients. Edema and rashes were seen in Group A patients, similarly, edema and insomnia were seen in Group B patients which was mild to moderate. Sodium hyaluronate was safe and effective for OA of knee when compared with methylprednisolone.