Treatment of osteoarthritis (OA) includes pain control and improvement of patients' function and quality of life. While conventional treatment such as non-steroidal anti-inflammatory drugs and simple analgesics may achieve these goals, their use is not without side-effects. The use of "natural remedies" and "folklore medicines" is therefore commonly practised by patients with OA. Lyprinol® is a lipid extract of the green-lipped mussel which is rich in omega-3 fatty acids and has previously been shown to have anti-inflammatory effects in both in vitro and animal studies. The aim of this study was to compare the effects of Lyprinol® with placebo on the signs and symptoms and patient quality of life in the treatment of knee OA. Eighty patients with knee OA were randomized to receive either Lyprinol® or placebo for six months. All were allowed paracetamol rescue treatment during the study and were reviewed at week 0, 2, 4, 8, 12, 18 and 24 for arthritis assessment and safety evaluation. Assessment of the patients' arthritis included the use of a 100 mm visual analog scale (VAS) for pain, patient's and physician's global assessment of arthritis, a validated Chinese version of the Oxford Knee Score (COKS), a validated Chinese version of the Arthritis Impact Measurement Scale 2-short form (CAIMS2-SF), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Improvement in almost all of the arthritis assessment parameters was observed in both groups of patients studied. However, there was a greater improvement in the perception of pain as measured by the VAS, and patients' global assessment of arthritis in those who took Lyprinol® when compared with controls from week 4 following adjustment for the change in the amount of paracetamol used between study visits. Patients who took Lyprinol® but not placebo also had improved scores in the CAIMS2-SF physical function and psychological status domains from week 4. However, changes in these scores did not differ significantly between the two groups at various study visits. When used over six months, Lyprinol® was safe and well tolerated with no serious side-effects reported. Further, there were no significant differences in the overall incidence of adverse reactions or withdrawal from study as a result of trial drug toxicity between Lyprinol® and placebo treated patients. In conclusion, Lyprinol®, a lipid extract of the green-lipped mussel, may be considered a safe option in the treatment of OA.