Objective To investigate the expressions of activating transcription factor 3 (ATF3) and ATF4, and their effects on γ-glutamylcysteine synthetase (γ-GCS) in lung tissues of patients with chronic obstructive pulmonary disease (COPD). Methods Non-cancerous lung tissue specimens ( 5 cm or above away from tumor) were collected from 40 lung cancer patients who underwent pulmonary lobectomy between December 2008 and December 2009. The patients were divided into a COPD group and a control group according to whether they were complicated with COPD. The clinical data were collected including the history in detail, physical examination, chest X-ray or lung CT, and pulmonary function test. The mRNA and protein expressions of ATF3, ATF4, and heavy subunit of γ-GCS (γ-GCS-HS) in lung tissues were detected by in situ hybridization and immunohistochemistry. At the same time, the interaction between ATF3, ATF4 and γ-GCS-HS protein was investigated by co-immunoprecipitation method. The correlation of ATF3 and ATF4 with γ-GCS-HS was analyzed. Results The mRNA and protein expressions of ATF3, ATF4 and γ-GCS-HS in lung tissues of the COPD group were strongly positive, and significantly higher than those in the control group (P＜0.01). The co-immunoprecipitation showed that ATF3 and ATF4 antibodies could cross the clear protein bands in the immune precipitation captured by γ-GCS-HS, and the intensity in the COPD group was significantly enhanced than that in the control group (P＜0.01). Correlation analysis showed that the protein expressions of ATF3 and ATF4 were significantly positively correlated with the mRNA and protein expression of γ-GCS-HS (allP＜0.01). The protein expressions of ATF3, ATF4 and γ-GCS-HS in lung tissues were positively correlated with FEV1%pred and FEV/FVC (P＜0.01). Conclusions Oxidative stress induces overexpression of ATF3 and ATF4 which may paly role in the pathogenesis of COPD. ATF3 and ATF4 may play antioxidative effect by affecting the mRNA and protein expression of γ-GCS.