Smokers have been reported to have an improved short-term prognosis after myocardial infarction when compared with nonsmokers. This study examines the effect of smoking status on infarct-related artery patency, a determinant of outcome, following thrombolytic therapy for acute myocardial infarction (AMI). To evaluate patency outcome by smoking status, the database of the Second Thrombolytic Trial of Eminase in Acute Myocardial Infarction was reviewed, and baseline characteristics were compared with infarct-related artery patency early (90 to 240 minutes) after thrombolysis in smokers versus nonsmokers. Smokers were younger (mean age 53 vs 59 years, p = 0.0001), more likely to be men (86 vs 73%, p = 0.008), normotensive (74 vs 58%, p = 0.004), to have an inferior infarction (66 vs 51%, p = 0.007), and tended to have higher hematocrits and fibrinogen levels than nonsmokers. Smokers had a significantly greater chance of achieving complete perfusion (Thrombolysis in Myocardial Infarction trial grade 3) (66 vs 51% p = 0.007) than nonsmokers, although the combination of grades 2 and 3 did not differ. After correcting for imbalances in baseline and angiographic variables, multivariate logistic regression identified smoking (odds ratio 1.8, p = 0.01) and infarct location (odds ratio 1.7, p = 0.03) as independent predictors of achieving grade 3 flow. The independent predictive component of smoking for achieving grade 3 patency after thrombolysis suggests the hypothesis that more active thrombogenic mechanisms may be operative in smokers, leading to a larger thrombus component that is more susceptible to lytic therapy.