Objectives: The aim of this study was to compare the clinical outcomes of acute ischemic stroke patients 80 years or older treated with intravenous recombinant tissue plasminogen activator (IV rt-PA), or endovascular intervention with or without IV rt-PA, or nonthrombolytic medical treatment. Methods: This study was a retrospective, nonrandomized, observational study of patients, admitted within 9 hours of symptom onset, at 3 academic, university-affiliated hospitals. The main outcome measures were neurologic improvement, defined by improvement in National Institutes of Health Stroke Scale score at 7 days or discharge of 4 or more, or achieving a score of 0; symptomatic and asymptomatic intracerebral hemorrhage; favorable outcome (discharge modified Rankin score 0-2); and in-hospital mortality. Results: A total of 44 patients received IV rt-PA, 46 received endovascular intervention with or without IV rt-PA, and 66 received nonthrombolytic medical treatment. IV rt-PA-treated patients had a significantly clinically higher chance of favorable outcome (odds ratio [OR], 5.6; 95% confidence interval [CI], 1.8-17.5), when compared with nonthrombolytic medical treatment. A significantly higher rate of neurologic improvement was observed among the IV rt-PA (7.2; 95% CI, 2.7-19.5) and endovascularly treated patients (5.8; 95% CI, 2-16.8) when compared with nonthrombolytic medical treatment. Conclusions: A prominently higher rate of neurologic improvement and favorable clinical outcome was observed among acute ischemic stroke patients 80 years or older treated with IV rt-PA or endovascular intervention when compared with nonthrombolytic medical treatment, supporting the use of acute thrombolytic therapies in this patient population when contraindications are not present.