Methotrexate is an antineoplastic drug used commonly in leukemia treatment. Because of becoming resistant to standard doses after 1970s, it is used intermediate or high doses. The complications of high doses are mucositis, vomiting, dermatitis exfoliativa, B-cell dysfunction, hepatotoxicity, nephrotoxicity and bone marrow depression. There were only two studies in literature about Stevens-Johnson syndrome occuring in two patients with acute lymphocytic leukemia and non-Hodgkin lymphoma after receiving high doses methotrexate and leukoverin. We have reported a two-year-old boy patient suffering from acute lymphocytic leukemia (ALL) developed a severe skin reaction two days after administration of high dose methotrexate. The skin lesions simulated Stevens-Johnson syndrome with ulceration of the oral mucosa and erythema multiforme-like target lesions.