The purpose of this study was to report severe cutaneous reactions in two patients related with leflunomide. A 13-year-old girl was treated with leflunomide for systemic lupus erythematosus. Three months later a progressive generalized blistering formation occurred and epidermolysis appeared on her skin. Methylprednisolone pulse therapy and intravenous immunoglobulin were used to control the severe cutaneous reactions. The patient recovered within 18 days. Another case is a 63-year-old woman who was treated with leflunomide for primary Sjögren's syndrome. Four months later widespread prunosus skin rash appeared on her skin. Methylprednisolone pulse therapy was also used to control the severe cutaneous reactions. The patient was recovered 11 days later. Our report suggests that an association between leflunomide intake and severe cutaneous reactions in rheumatic disease patients should be considered.