Thrombolytic therapy is the only approved therapy for acute ischemic stroke patients. As part of the European approval process, the Safe Implementation of Thrombolysis in Stroke – Monitoring Study (SITS-MOST) was demanded as a Phase IV study to evaluate the safety and efficacy of alteplase in a 3-h time-window. This article summarizes SITS-MOST and compares it with other Phase IV studies. Between 2002 and 2006, 6483 patients were included in 285 centers; median age was 68 years, median National Institutes of Health Stroke Scale (NIHSS) score was 12 and the median time-window was 140 min. The rate of symptomatic intracerebral hemorrhages, defined as parenchymal hemorrhage type 2 combined with a neurological deterioration of at least 4 points on NIHSS, was 1.7% within 24 h after treatment. Symptomatic hemorrhages as defined by the National Institute of Neurological and Communicative Disorders and Stroke criteria occurred in 7.3% of patients. The 3-month mortality was 11.3% and the rate of good clinical outcome (modified Rankin Score 0–2) was 55%. There were no major differences between experienced and inexperienced centers regarding safety or efficacy. The results of SITS-MOST are comparable with the results of the randomized placebo-controlled trials and other Phase IV studies such as standard treatment with Alteplase to Reverse Stroke and Canadian Alteplase for Stroke Effectiveness Study. They confirm that intravenous alteplase is safe and effective in routine clinical practice when used for acute stroke within 3 h of stroke onset, even in centers with little previous experience of thrombolytic therapy but only if the licensing approval criteria are strictly followed. These findings should encourage wider use of thrombolytic therapies for suitable stroke patients treated in stroke centers.