Abstract: Objective To explore the role of IL-6 in the progress of Estrogen(E2) promoting lung adenocarcinoma in mice and its possible mechanism. Methods Urethane-induced lung adenocarcinoma models of female Kunming mice were established, and divided as follows(n=9 in each group): the control, E2, E2+estrogen inhibitors(E2I), E2I, IL-6 and E2+IL-6 group. 16 weeks later, we sacrificed mice and tested weight changes, tumorigenicity, the total number of nodules, tumor grade, and lung indices. At the same time, we detected the content of E2/IL-6 in serum specimens by enzyme-linked immunoassay (ELISA), ERβ/IL-6 mRNA levels by RT-PCR, and the protein expression of ERβ, Akt, MAPK, p-ER beta, p-Akt, p-MAPK by Western blot. Results The pulmonary nodules rate in Kunming mice were 87.04% (47/54); the lung adenocarcinoma rate were 70.37%(38/54); the total number of nodules, tumor grade, and lung indices in E2 group were significantly higher than those in E2+E2I and E2I group (P<0.05); and above detection index in E2 group was significantly higher than those in E2+IL-6, IL-6 group and blank control group (P<0.05); E2 and IL-6 in control group had highly correlations(P<0.05). The expression of Akt, MAPK, ER beta, p-Akt, p-MAPK, p-ER beta and ER beta mRNA were consistent with the cancer statistics index (P<0.05). Conclusion IL-6 downregulating ER beta signaling pathways is found in E2 promoting the progress of lung adenocarcinoma in mice for the first time, which indicates that IL-6 in lung cancer may inhibit E2 to promote lung adenocarcinoma progression.