Estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Based on their previous findings, the authors sought to investigate whether estrogen and IGF-1 act synergistically to promote lung adenocarcinoma (LADE) development in mice. LADE was induced with urethane in ovariectomized Kunming mice. Tumor-bearing mice were divided into seven groups: 17-estradiol (E2), E2+fulvestrant (Ful; estrogen inhibitor), IGF-1, IGF-1+AG1024 (IGF-1 inhibitor), E2+IGF-1, E2+IGF-1+Ful+AG1024 and control groups. After 14 weeks, the mice were sacrificed, and then the tumor growth was determined. The expression of ER/ER, IGF-1, IGF-1R and Ki67 was examined using tissue-microarray-immunohistochemistry, and IGF-1, p-ER, p-IGF-1R, p-MAPK and p-AKT levels were determined based on Western blot analysis. Fluorescence-quantitative polymerase chain reaction was used to detect the mRNA expression of ER, ER2 and IGF-1R. Tumors were found in 93.88% (46/49) of urethane-treated mice, and pathologically proven LADE was noted in 75.51% (37/49). In the E2+IGF-1 group, tumor growth was significantly higher than in the E2 group (p < 0.05), the IGF-1 group (p < 0.05) and control group (p < 0.05). Similarly, the expression of ER, p-ER, ER2, IGF-1, IGF-1R, p-IGF-1R, p-MAPK, p-AKT and Ki67 at the protein and/or mRNA levels was markedly higher in the ligand group than in the ligand + inhibitor groups (all p < 0.05). This study demonstrated for the first time that estrogen and IGF-1 act to synergistically promote the development of LADE in mice, and this may be related to the activation of the MAPK and AKT signaling pathways in which ER1, ER2 and IGF-1R play important roles. What's new? The present study demonstrated for the first time that estrogen and insulin-like growth factor-1 (IGF-1) can synergistically promote the development of lung adenocarcinoma in mice. Such effect might be attributed to the activation of the MAPK and AKT signaling pathways, with the key molecules ER1, ER2, and IGF-1R playing important roles. The results further revealed that the combined use of estrogen receptor (ER) and IGF-1R inhibitors may suppress lung adenocarcinoma growth to a greater extent than either inhibitor alone. Blocking multiple targets in the estrogen and IGF-1 signaling pathways may thus have substantial therapeutic potential in lung cancer.