Background and Purpose—The impact of smoking on prognosis after stroke is controversial. We aimed to assess the relationship between smoking status and stroke outcome after intravenous thrombolysis in a large cohort study by adjusting for potential confounders and incorporating recanalization rates.Methods—In a prospective observational multicenter study, we analyzed baseline and outcome data of consecutive patients with acute ischemic stroke treated with intravenous thrombolysis. Using uni- and multivariable modeling, we assessed whether smoking was associated with favorable outcome (modified Rankin Scale score of 0–1) and mortality. In addition, we also measured the occurrence of symptomatic intracranial hemorrhage and recanalization of middle cerebral artery. Patients reporting active cigarette use were classified as smokers.Results—Of 1865 patients, 19.8% were smokers (n=369). They were younger (mean 63.5 versus 71.3 years), less often women (56% versus 72.1%), and suffered less often from hypertension (61.3% versus 70.1%) and atrial fibrillation (22.7% versus 35.6%) when compared with nonsmokers. Favorable outcome and 3-month mortality were in favor of smokers in unadjusted analyses (45.8% versus 39.5% and 9.3% versus 15.8%, respectively), whereas symptomatic intracranial hemorrhage was comparable in both cohorts. Smoking was not associated with clinical outcome and mortality after adjusting for confounders (odds ratio, 1.20; 95% confidence interval, 0.91–1.61; P=0.197 and odds ratio, 1.08; 95% confidence interval, 0.68–1.71; P=0.755, respectively). However, smoking still independently predicted recanalization of middle cerebral artery in multivariable analyses (odds ratio, 2.68; 95% confidence interval, 1.11–6.43; P=0.028).Conclusions—Our study suggests that good outcome in smokers is mainly related to differences in baseline characteristics and not to biological effects of smoking. The higher recanalization rates in smokers, however, call for further studies.