Previous studies have shown that undenatured type II collagen (UC-II) is effective in the treatment of rheumatoid arthritis, and preliminary human and animal trials have shown it to be effective in treating osteoarthritis (OA). The present clinical trial evaluated the safety and efficacy of UC-II as compared to a combination of glucosamine and chondroitin (G+C) in the treatment of OA of the knee. The results indicate that UC-II treatment was more efficacious resulting in a significant reduction in all assessments from the baseline at 90 days; whereas, this effect was not observed in G+C treatment group. Specifically, although both treatments reduced the Western Ontario McMaster Osteoarthritis Index (WOMAC) score, treatment with UC-II reduced the WOMAC score by 33% as compared to 14% in G+C treated group after 90 days. Similar results were obtained for visual analog scale (VAS) scores. Although both the treatments reduced the VAS score, UC-II treatment decreased VAS score by 40% after 90 days as compared to 15.4% in G+C treated group. The Lequesne's functional index was used to determine the effect of different treatments on pain during daily activities. Treatment with UC-II reduced Lequesne's functional index score by 20% as compared to 6% in G+C treated group at the end of 90-day treatment. Thus, UC-II treated subjects showed significant enhancement in daily activities suggesting an improvement in their quality of life.