Efficacy of Methotrexate on Pain Severity Reduction and Improvement of Quality of Life in Patients with Moderate to Severe Knee Osteoarthritis. BACKGROUND: Knee osteoarthritis (OA) leads to low quality of life due to pain and limitation in daily activities. Recent studies indicated that Methotrexate (MTX) could reduce pain due to its anti-inflammatory effects. OBJECTIVES: In this study, the researchers aimed at evaluating the efficacy of MTX in pain control and improvement of quality of life in patients with moderate to severe knee OA. METHODS: In this randomized clinical trial, 100 patients with moderate to severe knee OA were allocated to receive MTX (n = 50) 7.5 mg weekly to be increased to 15 mg weekly after first months or placebo (n = 50) for six months. Pain severity was measured using the numerical rating scale (NRS), so was functional status by Western Ontario and McMaster Universities Arthritis Index (WOMAC) and quality of life by SF-12 questionnaire before the treatment, and three months and six months after the intervention. The results were compared between the groups subsequently. Nine patients from the MTX group were excluded due to the use of corticosteroids during the treatment period. RESULTS: The MTX group compared to the placebo group had significant improvement in pain severity and quality of life during six months and WOMAC parameters at three and six months after the intervention. The need for NSAIDS was slightly higher in the placebo group with no significant difference (22% versus 36%, P = 0.14). The MTX adverse effects were not observed. CONCLUSIONS: Treatment of moderate to severe knee OA with MTX could reduce pain severity and improve functional status and quality of life in OA patients.