BACKGROUND Recombinant tissue plasminogen activator (rt-PA) is the first-line therapy demonstrated to be safe and effective in acute ischemic stroke. People with pre-existing severe dementia or physical disability are usually excluded from rt-PA. The aim of our study was to investigate rt-PA safety and effectiveness in acute stroke with pre-existing disability (mRS ≥ 2). METHODS The study encompassed 35 acute ischemic stroke patients with mRS ≥ 2 treated with rt-PA. In order to assess the differences in clinical outcome in three disability groups (mRS = 2; 3; 4/5), the following parameters were evaluated: intracerebral hemorrhage, mortality, NIHSS, ΔNIHSS and mRS. RESULTS Baseline-NIHSS and age were not significantly different among groups. Mortality was higher in the pre-morbid mRS 4/5 group (44%) than in the pre-morbid mRS2 (16.7%) and mRS 3 groups (21.4%). In survived patients, median ΔNIHSS% was higher in the mRS2 and 3 groups (-63.3% and -92.3%, respectively) than in the mRS4/5 group (-9.1%). The 247 rt-PA treated subjects with mRS < 2 in the same period showed lower mortality rate (4.7%), lower sICH (5%), lower mRS at discharge (median 1; range 0-6) and similar ΔNIHSS% (-75%). CONCLUSIONS Patients with mRS 2 and 3 may benefit from rt-PA with a moderate risk of sICH and mortality.