In patients with acute ischemic stroke, does intravenous t-PA administered within 3 h of symptom onset improve clinical outcomes? The landmark NINDS randomized controlled trial assessed the efficacy and safety of intravenous tissue plasminogen activator (t-PA) administered within 3 h of symptom onset in patients with acute ischemic stroke. The trial was conducted in two parts. Part 1 focused on early neurological improvement at 24 h, while Part 2 evaluated long-term functional outcomes at 90 days. Patients receiving t-PA achieved significantly greater functional independence at 3 months, compared to those receiving a placebo. Notably, improvements were observed across four validated scales and a global test statistic. The incidence of symptomatic intracerebral hemorrhage was higher in the t-PA group. However, there was no difference in the 90-day mortality between the two groups. The study provided compelling evidence that early administration of tPA improves long-term outcomes in acute ischemic stroke within a 3-h therapeutic window. These findings represented a paradigm shift in the management of acute stroke, highlighting the critical importance of early recognition and treatment to optimize neurological recovery.