Objective: To evaluate the efficacy and safety of Xinfeng capsule (XFC) in patients with osteoarthritis (OA)., Methods: This was a multicenter, double-blinded, randomized, controlled, clinical trial. Patients with OA were assigned to the XFC group [treated with XFC and a glucosamine (GS) placebo, n = 129] or the GS group (treated with GS and an XFC placebo, n = 126). Both groups were treated for 4 weeks. The primary endpoint was the difference between the two groups in the Western Ontario and McMaster Universities OA (WOMAC) index total score at 4th week. The secondary endpoints were the visual analogue scale for pain, Lequesne index, function influence index rating, quality of life as assessed by the Short Form-36, erythrocyte sedimentation rate, and C-reactive protein concentration at baseline and at second week and 4th week. Bone mineral density were checked by X ray absorptiometry at baseline and 4th week., Results: After 4 weeks of treatment, all patients in both groups showed similar significant improvements compared with baseline. There were no significant differences between groups regarding pain relief, bilateral femoral bone mineral density, and laboratory indices such as erythrocyte sedimentation rate and C-reactive protein concentration. Both groups had a significantly lower function influence index rating score and curative effect for each sign/symptom in week 4 than in week 0, and these changes did not significantly differ between groups. XFC was superior to GS in improving the WOMAC index total score, WOMAC scores for function and stiffness, integrated symptoms, physiological function, energy, emotional function, mental health, and health?changes. Fourteen adverse reactions were reported, and the incidence of adverse reactions did not significantly differ between groups. The most common adverse reactions were hepatic impairment, kidney functional damage, gastrectasia, and facial skin allergy. The types of adverse reactions did not differ between groups., Conclusion: XFC is effective and safe in the treatment of OA. XFC was superior to GS in improving the WOMAC index total score, WOMAC scores for pain, stiffness, and function, visual analogue scale for pain, Lequesne index, and Short Form-36 quality of life.