Methotrexate induced Stevens-Johnson syndrome (SJS) is rare but life-threatening cutaneous reaction. This is a case report of two 14-year-old girls with methotrexate (MTX)-induced Stevens-Johnson syndrome (SJS). Both girls received chemotherapy with MTX in the treatment of osteosarcoma and then developed SJS. They showed cutaneous and mucosal erosions, macular and purplish rash, and ulceration in the cutaneous and mucosal areas. The full spectrum of all mucous membranesinvolved is less than 10% of the body surface area in the two patients.The diagnosis of SJS is based on clinical features and there are no universally accepted diagnostic criteria. Prompt withdrawal of causative drugs should be a priority and the re-exposure of culprit drug is not recommended.Corticosteroid at a dose of 1 mg / kg / day was administered to them and they both recovered from SJS. MTX is known as a drug that can induce SJS. So, it is rare but is not extremely rare.