Objectives: The objectives of this study were to determine the efficacy and safety of Derris scandens Benth extracts in pain reduction and functional improvement in patients with knee osteoarthritis (OA).Design: This was a prospective, randomized, controlled trial, single-blinded (assessor).Settings: The study was conducted at the Rehabilitation Medicine Department, Siriraj Hospital.Subjects: One hundred and seven (107) patients with primary OA knee who had pain score of ≥5 were recruited.Interventions: Patients were randomized to receive naproxen 500 mg/day or Derris 800 mg/day for 4 weeks.Outcome measurements: Western Ontario McMaster Osteoarthritis Index (WOMAC) scores and 6-minute walking distance were the outcome measurements.Results: Fifty-five (55) and 52 patients were randomized to Derris and naproxen groups, respectively. The mean differences of all WOMAC scores between 2 groups at week 4 adjusted by week 0 were within ± 1 point. The mean scores of the aforementioned outcomes at weeks 0, 2, and 4 were significantly improved compared to the baseline values. There was no difference of WOMAC scores between groups. The gastrointestinal irritation and dyspepsia were observed more often in the naproxen than in the Derris group.Conclusions: Derris scandens Benth extracts were efficacious and safe for the treatment of knee OA.