Objective To investigate the effect of S-adenosyl-l-methionine (SAM) on oxidative stress and alveolar septal cell apoptosis in mice with emphysema after smoking cessation. Methods Twenty-two male SPF C57BL/6J mice aged 6 - 8 weeks were randomly divided into 4 groups, ie. a healthy control group, an emphysema group, a smoking cessation group, and a SAM intervention for 8 weeks after smoking cessation group, with 8 mice in each group. The mice model of emphysema was established by intraperitoneal injection of cigarette smoke extract (CSE) combined with cigarette smoke exposure. Smoking cessation started after the emphysema model was successfully constructed and lasted for 8 weeks. After smoking cessation, the mice in SAM intervention groups were intraperitoneally injected with SAM mg·kg–1·d–1 for 8 weeks. The right lung sections of the mice were taken for hematoxylin-eosin staining to observe pathological changes, and the mean linea rintercept (MLI) and mean alveola rnumber (MAN) of lungs were measured. The concentrations of malondialdehyde (MDA), superoxide-dismutase (SOD) and glutathione (GSH) in alveolar lavage fluid of left lung were detected by spectrophotometry. Terminal deoxynucleotidyl transferasemediated dUTP nick end labeling (TUNEL) technique was carried out to detect the alveolar septal cells apoptosis. Results MLI, apoptosis index of alveolar septal cell and MDA concentration in bronchoalveolar lavage fluid (BALF) increased significantly in the emphysema group compared with healthy controls, increased significantly in the smoking cessation group compared with the emphysema group, and decreased in the SAM intervention group compared with the smoking cessation group (all P<0.05). GSH concentration and SOD activity in BALF and MAN was significantly lower in the emphysema group compared with the healthy control group, significantly lower in the smoking cessation group compared with the emphysema group, and significantly higher in the SAM intervention group compared with the smoking cessation group (all P<0.05). Conclusions Lung histopathology and apoptosis of alveolar septal cells in emphysema mice progress continuously after smoking cessation. SAM may reduce oxidative stress and improve apoptosis of alveolar septal cells, so as to protect emphysema mice after smoking cessation.