A 57-year-old male developed an adenocarcinoma lung cancer in November 2003. He received the full course chemotherapy but without a significant regression. The targeted therapy gefitinib was prescribed 2 years after diagnosis, producing a very good partial response. However, brain metastasis was diagnosed. A whole brain irradiation was performed for 37.5Gy with a fraction size of 2.5Gy and gefitinib was replaced with erlotinib on the 5th day after radiation therapy commenced for disease progressing. Unexpectedly, the patient developed a severe skin reaction in the region exposed to the radiation field, and a bilateral subdural hemorrhage, following radiation therapy. The reaction was thought to be triggered by the combination of radiation and epidermal growth factor receptor tyrosine kinase inhibitors, which may be responsible for hypersensitizing the radiation response in normal tissue in the unique individual.