Background: Smoking has been shown to reduce health-related quality of life (HRQOL) in patients with coronary artery disease (CAD) undergoing percutanous coronary intervention (PCI) either by means of balloon angioplasty or with the use of bare-metal stents (BMS). Drug-eluting stents (DES) have now been widely used and are related to substantial reduction of restenosis and significantly improved HRQOL compared with BMS. This study aimed to evaluate the effects of smoking on HRQOL in patients after PCI in DES era. Methods: A cohort of 649 patients admitted for CAD and treated with drug-eluting stents were included in this prospective, observational study. Patients were classified as non-smokers (n = 351, 54.1%), quitters (n = 126, 19,4%), or persistent smokers (n = 172, 26.5%) according to their smoking status at the time they first admitted to hospital and during the first year of follow-up. Each patient was prospectively interviewed at baseline, 6 months and 1 year following PCI. HRQOL was assessed with the use of Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Results: For the overall population, HRQOL scores at 1-year follow-up were significantly higher than baseline for all 8 domains. At 1-year follow-up, the HRQOL scores in persistent smokers were still lower than that in non-smokers in 6 domains except for bodily pain and mental health, and than that in quitters in 5 domains except for bodily pain, role emotional and mental health. There were no significant differences with regard to the scores between non-smokers and quitters except role emotional for which non-smokers had higher scores. After adjustment, persistent smokers demonstrated significantly less improvements in HRQOL than non-smokers in 6 domains except for bodily pain and social functioning and significantly less improvement than quitters for general health. Improvements of quitters were comparable to that of non-smokers in all domains. Multivariate linear regression analyses showed persistent smoking was an independent risk factor for PCS and MCS improvements. Conclusions: Persistent smoking substantially diminishes the potential quality-of-life benefits of DES. Efforts should be made to promote smoking cessation after DES implantation which could greatly improve the health quality outcomes.