Background and Purpose— Renal dysfunction (RD) is associated with poor prognosis after stroke. We assessed the effects of RD on outcomes and interaction with low- versus standard-dose alteplase in a post hoc subgroup analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). Methods— A total of 3220 thrombolysis-eligible patients with acute ischemic stroke (mean age, 66.5 years; 37.8% women) were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset. Six hundred and fifty-nine (19.8%) patients had moderate-to-severe RD (estimated glomerular filtration rate, <60 mL/min per 1.73 m ² ) at baseline. The impact of RD on death or disability (modified Rankin Scale scores, 2–6) at 90 days, and symptomatic intracerebral hemorrhage, was assessed in logistic regression models. Results— Compared with patients with normal renal function (>90 mL/min per 1.73 m ² ), those with severe RD (<30 mL/min per 1.73 m ² ) had increased mortality (adjusted odds ratio, 2.07; 95% confidence interval, 0.89–4.82; P =0.04 for trend); every 10 mL/min per 1.73 m ² lower estimated glomerular filtration rate was associated with an adjusted 9% increased odds of death from thrombolysis-treated acute ischemic stroke. There was no significant association with modified Rankin Scale scores 2 to 6 (adjusted odds ratio, 1.03; 95% confidence interval, 0.62–1.70; P =0.81 for trend), modified Rankin Scale 3 to 6 (adjusted odds ratio, 1.20; 95% confidence interval, 0.72–2.01; P =0.44 for trend), or symptomatic intracerebral hemorrhage, or any heterogeneity in comparative treatment effects between low-dose and standard-dose alteplase by RD grades. Conclusions— RD is associated with increased mortality but not disability or symptomatic intracerebral hemorrhage in thrombolysis-eligible and treated acute ischemic stroke patients. Uncertainty persists as to whether low-dose alteplase confers benefits over standard-dose alteplase in acute ischemic stroke patients with RD. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01422616.