Cigarette smoking is known to be deleterious to patients with coronary artery disease; however, the effect of smoking on vascular responses after coronary drug-eluting stent implantation is unknown. We sought to examine vascular response after sirolimus-eluting stent implantation in patients with ongoing smoking using optical coherence tomography, compared with former smokers and nonsmokers. We identified 181 sirolimus-eluting stents in 140 subjects who underwent follow-up optical coherence tomography imaging. Subjects were divided into 3 groups: current smokers (n = 28), former smokers (n = 35), and nonsmokers (n = 77). Stent strut coverage, neointimal characteristics, and strut malapposition were evaluated. The incidence of uncovered stent struts was significantly higher in nonsmokers compared with current smokers (13.3 ± 13.3% vs 6.7 ± 8.3%; p = 0.001). On qualitative evaluation of neointimal morphology, the prevalence of heterogeneous neointima was higher in current smokers (71.9%) than in former smokers (36.0%) or nonsmokers (10.1%) (p = 0.004 and p <0.001, respectively). There was no difference in the incidence of malapposition among the 3 groups. Multivariate modeling showed that current smoking was negatively associated with the presence of uncovered struts (odds ratio 0.33; 95% confidence interval 0.14 to 0.79; p = 0.013) and positively associated with the presence of heterogeneous neointima (odds ratio 9.47; 95% confidence interval 3.79 to 23.72; p <0.001). In conclusion, the incidence of strut coverage was higher in current smokers compared with nonsmokers. However, the pattern of neointima was more heterogeneous in current smokers.