OBJECTIVE: Leflunomide is the newest disease-modifying anti-rheumatic drug (DMARD) that is known to have an equivalent clinical efficacy and tolerability to methotrexate (MTX). Previous studies reported that a co-treatment with MTX and leflunomide can induce additive clinical improvements in RA patients. However, a previous study also demonstrated a reversible elevation of the transaminase levels in up to 63% of patients administered a combination treatment of leflunomide and MTX. This study examined the hepatotoxicity of a combination treatment of MTX and leflunomide. METHODS: From March, 2004, to February, 2006, 203 patients who had been treated in 3 rheumatology clinics, Goyang city, South Korea, were reviewed retrospectively. The data showed that 38.92% of patients scored higher than grade 1 hepatotoxicity and 6.90% of patients scored higher than grade 2 according to the NCI/NIH (National Cancer Institute/National Institutes of Health) Common Toxicity Criteria. RESULTS: The median onset time of hepatotoxicity was 5.91 months after treatment. Leflunomide administration was stopped in 39 patients due to several adverse reactions. Among the 39 patients, hepatotoxicity was observed in only 20.51%, suggesting that the hepatotoxicity was not more frequent than expected. Hepatotoxicity did not increase in proportion to the dose of leflunomide and MTX, age, gender, and disease activity. CONCLUSION: These results indicate that a combined treatment of leflunomide and MTX can be used safely by monitoring the liver enzyme, particularly in the first six months.