Leflunomide is an inhibitor of dihydro-orotate dehydrogenase (DHODH), a mytochondrial enzyme important for de novo synthesis of pyrimidine ribonucleotides. It blocks the proliferation of human T lymphocytes thus leading to the arrest in the G1/S phase of the cell cycle and to the interruption of T lymphocytes clonal expansion. Lefl unomide has been shown to inhibit the activation of NF-kB being able to block TNF-mediated NF-kB activation in a dose-and time dependent manner. Clinical trials have shown similar effi cacy to methotrexate. The side effects are mainly at the gastrointestinal, lung and liver level. Effi cacy and tolerability have been shown to be similar in adult and elderly patients.