After excluding the corresponding drug contraindications of leflunomide and methotrexate, patients with the condition of need can be treated with leflunomide and methotrexate at the same time, but should be regularly tested for liver function. Leflunomide and methotrexate are both immunosuppressants, leflunomide is mainly used for the treatment of adult rheumatoid arthritis; methotrexate can be used for the treatment of acute leukemia, lung cancer, psoriasis, cervical cancer, testicular cancer and other diseases, leflunomide can be used in combination with methotrexate for the treatment of rheumatoid arthritis and achieve better results. The main adverse effects of leflunomide are diarrhea, pruritus, reversible elevation of liver enzymes (ALT and AST), alopecia, and rash. Methotrexate adverse reactions include nausea, vomiting, abdominal pain, jaundice, bone marrow suppression, alopecia, skin redness, itching or rash, and infections. It is contraindicated in patients who are hypersensitive to leflunomide and its metabolites and in patients with severe hepatic impairment. It is contraindicated in patients with high hypersensitivity to methotrexate. The combination of these two drugs can be treated after the exclusion of contraindications to the drug. Note that during the initial phase of the use of leflunomide should be checked regularly for ALT and leukocytes at intervals that depend on the patient’s condition, and with caution in patients with severe hepatic impairment and definite positive serologic indicators of hepatitis B or C. Prolonged use of methotrexate carries a potential risk of secondary tumors, as well as amenorrhea and sperm reduction or deficiency, especially after long-term application of higher doses. Leflunomide and methotrexate should be used under the guidance of a physician, and patients are advised to go to the relevant departments of regular hospitals for detailed consultation and treatment as prescribed by the doctor.