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Introduction: osteoarthritis is a chronic and progressive disease. It affects over 30 % of people older than 60. Osteoarthritis is currently recognized as a multifactorial disease. Various conservative treatments are used in the management of knee osteoarthritis (NSAIDs, analgesics, and intra-articular therapy). We conducted a randomized clinical trial to determine if a 10 g therapy of hydrolyzed collagen along with 100 mg fucoidan (Hydroidan pro, Acten, Switzerland) is more effective than intra-articular therapies. Methods: we divided patients into 3 groups. The first group received 23 g of ACTEN®, daily, for 3 months. The other groups received a single intra-articular injection of hyaluronic acid (5 ml) or platelet-rich plasma (3 ml). We used the WOMAC scale, the SF-12 scale, and the VAS for pain at baseline, and 4, 12, and 24 weeks later. Results: we enrolled 108 patients with grade II-III knee osteoarthritis who underwent a 24-week follow-up study. The mean age was 57 years (53-65). The three groups showed low scores in the WOMAC group (p < 0.001). The collagen with fucoidan group had lower WOMAC and VAS scores compared with the hyaluronic acid and platelet-rich plasma groups at 24 weeks (p < 0.001). Conclusions: collagen along with fucoidan taken orally, daily, for 12 weeks seem to have better results in the WOMAC and VAS scales compared with intra-articular therapies such as hyaluronic acid or platelet-rich plasma. Combined oral and intra-articular therapies should be tried to determine their efficacy profile. [ABSTRACT FROM AUTHOR]