Background: It is common practice to withhold intravenous thrombolysis (IVT) for acute ischemic stroke in patients with preexisting disabilities. To test the hypothesis of an association of IVT and good clinical outcome also in patients with preexisting disabilities without an increase in mortality we analyzed data of 52,741 patients (15,317 treated with IVT) depending on prestroke Rankin Scale (pRS) score. Methods: We performed an observational study based on a consecutive stroke registry covering 10.8 million inhabitants. The outcome at discharge of stroke patients admitted in the time window of potential eligibility for IVT (<4.5h after stroke onset) was compared between patients treated and not treated with thrombolysis, stratified by pRS. Logistic regression analysis was used to estimate adjusted odds ratios (OR) along with 95% confidence intervals (CI) for favorable clinical outcome, defined as returning to the baseline pRS score or a score of 0 or 1 and mortality. Sensitivity analyses for subgroups of mildly and severely affected stroke patients were performed and influence of treatment duration was assessed. Results: Among included patients IVT rates were 32% for patients with pRS 0-1 and 20% for patients with pRS 2-5. IVT in patients with pRS of 0-4 was associated with a higher chance of returning to the baseline pRS (or a modified RS of 0/1), with ORs ranging between 1.42 (pRS 2; CI 1.16-1.73) and 1.73 (pRS 0; CI 1.61-1). The OR observed in patients with a pRS of 5 was 0.65 (CI 0.25-1.70). Observed associations remained consistent in sensitivity analyses. Subgroup analyses revealed no evidence of bias due to potential floor and ceiling effects. No evidence of elevated in-hospital mortality of patients treated with thrombolysis was observed. Conclusions: Our study suggests that IVT can be effective even in patients with severe preexisting disabilities, provided that they were not bedridden before stroke onset. Withholding IVT on the sole ground of prestroke disabilities may not be justified.