The 5-year survival rate of lung cancer patients are only 15% [1]. Adenocarcinomas (AC) represent 40 to 76% of Non-Small Cell Lung Cancer Cells [1]. Tobacco use and asbestos exposure are known as the most significant risk factors leading to lung cancer. However, the prognosis of the patients with the same stage of lung cancer is variable. Therefore, it is of great importance to identify novel biomarkers to predict the prognosis of lung cancer patients. Furthermore, tissue homeostasis is based on a balance between cell proliferation and apoptosis. Calcium is known to play an important role in regulation of cell proliferation and apoptosis. ORAI channels play a major role in providing calcium influx. There are 3 isoforms: ORAI1, 2 and 3. ORAI3 is involved in the proliferation of lung cancer cells [2]. In breast cancer, it has been reported that ORAI3 is an estrogen receptor α (ERα) and that EGF-regulates its activity [3]. Moreover, both ERα and EGFR play a significant role in the growth of human lung carcinomas [4-5]. The aim of the present study was to investigate the ORAI3 expression in primitive lung AC paraffin-embedded (n=200) in relation to ERα and EGFR and its potential relevance to clinicopathological variables and prognosis. ORAI3 staining was present in 66.5% (N=133/200) of all the AC. Statistical analysis showed that overexpression of ORAI3 was significantly associated with tobacco use, asbestos exposure, necrosis tumor, visceral pleura invasion, ERα and EGFR. The Kaplan-Meier survival analysis showed that the expression of ORAI3 was related to the poor overall survival (OS) (expression, N=133/200, mean survival = 40.71 months vs no expression, N=67/200, mean survival = 95.6 months; p<0.001) and metastatic progression-free survival (MP-FS) (expression, N=133/200, mean survival = 27.21 months vs no expression, N=67/200, mean survival = 69.52 months; p<0.001) of patients with lung AC. Multivariate Cox analysis showed that ORAI3 was an independent prognostic factor for both OS and MP-FS of patients with lung AC.To conclude, we highlight the major role of ORAI3 regulation by ERα and EGFR in lung AC. We show, for the first time, that the overexpression of ORAI3 was associated with environmental risk factors, histological variables and poor prognosis in lung AC and thus may serve as a new molecular marker to predict the prognosis of lung AC patients.