Abstract: The disease-modifying antirheumatic drug leflunomide is associated with hepatic toxicity as a side effect. This study aimed to lesser hepatic toxicity of leflunomide by using silymarin in combination with leflunomide to avoid the hepatic toxicity resulting from using leflunomide in treatment of rheumatoid arthritis. Drugs were orally administered after arthritis was induced by subplantar injection of 0.1 mL Freund's complete adjuvant. Oral administration of leflunomide and silymarin inhibited the dermal hypersensitivity of adjuvant-induced arthritis and significantly reduced the paw oedema in comparison to the control group. This combination normalized serum nitric oxide concentration. Leflunomide caused a significant elevation of the serum liver enzymes activity Glutamate-Oxalate Transaminase and Glutamate-pyruvate Transaminase which were improved by silymarin co-treatment. These results revealed that silymarin has positive effect on adjuvant-induced arthritis and marked antioxidant activity which minimized the toxic effect of leflunomide on the liver. In conclusion silymarin could be used in combination with leflunomide to minimize its toxic effect on liver.