BACKGROUND: Available medication for pain and joint stiffness release in osteoarthritis (OA) often gives considerable side effects. Undenatured type II collagen (UC-II) has been considered as a treatment for OA for its ability to prevent the progress of articular cartilage damage. Hence, this study aimed to evaluate the efficacy and safety of UC-II in modulating knee joint function. METHODS: This was a randomized, double-blind, placebo-controlled study involving 102 OA subjects. Subjects were randomized into two groups: receiving an oral daily dose of 40 mg/day UC-II or placebo containing microcrystalline cellulose for 90 days. Efficacy was evaluated by using the Western Ontario McMaster Osteoarthritis Index (WOMAC), Lequesne’s Functional Index (LFI), and Visual Analogue Scale (VAS) score on day-1, -7, -30, -60, and -90. Safety was evaluated by assessing the adverse events (AEs) and abnormal laboratory findings. RESULTS: The WOMAC total score showed a significant difference between the UC-II group vs. the placebo group from day-7 (p