Background: There are many types of arthritis, but osteoarthritis (OA) is one of the most frequent. IA injections of corticosteroids into the knee joint may improve pain and impairment by relieving joint inflammation. Purpose: To evaluate the effectiveness and safety of hylastan, a novel viscosupplements, with a single intra-articular corticosteroid injection in the treatment of knee osteoarthritis pain (OA). Because of its large molecular weight, the sodium hyaluronate in Hylastan is more likely to stay in the joint for an extended period of time than other viscosupplements. Methods: Multicentered based randomized quasi-experimental comparative study was performed in Shah Mokhdum Medical College, Rajshahi, Bangladesh, from January 2019 to December 2021. Enrolled patients aged ≥40 years. Patients were randomized 1:1:1 to one of three arms: 2 X 4 mL hylastan (n = 129; arthrocentesis then IA hylastan Day 0, same treatment Week 2); 1 X 4 mL hylastan (n = 130; arthrocentesis then IA hylastan Day 0, arthrocentesis only Week 2); steroid (n = 132; arthrocentesis then IA methylprednisolone acetate 40 mg Day 0, arthrocentesis only Week 2). The primary clinical outcome measure was changed from baseline in WOMAC A pain score overall postbaseline visits to Week 26. Results: Statistically significant pain reduction was observed in all three arms, with similar mean (95 % CI) changes in WOMAC A: 2 X 4 mL hylastan -0.9 (-1.0, -0.7); 1 X 4 mL hylastan -0.8 (-0.9, -0.7); steroid -0.9 (-1.0, -0.8); all p < 0.0001 versus baseline. Changes in secondary outcomes were similar in all three arms. Target knee adverse events were comparable for all treatments. Conclusions: An acceptable safety profile and effective pain relief were found with both IA hylastan injection regimens. The hypothesis of better pain relief with IA hylastan was not met compared to IA corticosteroid. The effectiveness and safety of hylastan compared to other viscosupplements require more investigation. Level of evidence Therapeutic study, Level I.