Background: In non-small cell lung cancer (NSCLC), estrogen (E2) significantly promotes NSCLC cell growth via estrogen receptor beta (ER beta). Discovery and elucidation of the mechanism underlying estrogen-promoted NSCLC progression is critical for effective preventive interventions. IL6 has been demonstrated to be involved in the development, progression and metastasis in several cancers and IL6 overexpression is associated with poor prognosis in NSCLC. However, the exact role played by IL6 in estrogen-promoted NSCLC progress remain unknown. Here, we evaluated the expression and biological effects of IL6 in NSCLC cells when treated with E2 and explored the underlying mechanism of IL6 in E2-promoted NSCLC progression. Methods: Expression of ER beta/IL6 in 289 lung cancer samples was assessed by immunohistochemistry. Matched samples of metastatic lymph node and primary tumor tissues were used to quantify the expression of ER beta/IL6 by western blot. Expression levels of IL6 in NSCLC cells were quantified by western blotting, ELISA, and immunofluorescence staining. The effects of IL6 stimulated by E2 on cell malignancy were evaluated using CCK8, colony formation, wound healing and transwell. Furthermore, overexpression and knockdown ER beta constructs were constructed to measure the expression of IL6. The effects of IL6 stimulated by E2 on tumor growth were evaluated using a urethane-induced adenocarcinoma model. In addition, a xenograft mouse model was used to observe differences in ER beta subtype tumor growth with respect to IL6 expression. Results: IL6/ER beta expression were significantly increased in lung cancer. Higher IL6/ER beta expression was associated with decreased differentiation or increased metastasis. IL6 was an independent prognostic factor for overall survival (OS), higher IL6 expression was associated with decreased OS. Furthermore, ER beta regulates IL6 expression via MAPK/ERK and PI3K/AKT pathways when stimulated by E2 and promotes cell malignancy in vitro and induced tumor growth in vivo. Finally we confirm that ER beta isolation 1/5 is essential for E2 promotion of IL6 expression, while ER beta 2 not. Conclusions: Our findings demonstrate that E2 stimulates IL6 expression to promote lung adenocarcinoma progression through the ER beta pathway. We also clarify the difference in each ER beta subtype for E2 promoting IL6 expression, suggesting that ER beta/IL6 might be potential targets for prognostic assessment and therapeutic intervention in lung cancer.