Estrogen receptor (ER) has been detected in some specimens of lung cancer. Estrogen has an effect on the growth of lung cancer cell lines. An inverse relationship between ER and epithelial growth factor receptor (EGFR) was reported in pre-clinical data. A 70-year-old female with lung adenocarcinoma, who achieved a partial response by gefitinib, underwent estrogen replacement for menopause-associated symptoms during gefinitib therapy. Lung nodules enlarged with 1-month estrogen use and regressed 6 weeks after the end of estrogen therapy. To our knowledge, this is the first case report regarding the interaction between estrogen and EGFR inhibitors.