Background&Purpose: There are limited data directly comparing acute reperfusion therapies (RPT) for the treatment of acute ischemic stroke (AIS) in the setting of randomized controlled trials. We conducted a comprehensive meta-analysis of available clinical studies of acute RPT to indirectly compare them using a benefit-to-risk analysis. Subjects&Methods: We abstracted data from 16 RPT studies evaluating intravenous thrombolysis (IVT) using alteplase or tenecteplase (TAAIS, NINDS), sonothrombolysis (CLOTBUST) intra-arterial thrombolysis (PROACT I&II, IMS III, SYNTHESIS pilot&expansion study) and acute thrombectomy/thromboaspiration using different retrievers (MERCI, Multi-MERCI, PENUMBRA Pivotal Stroke Trial & Post Market Experience, SWIFT, TREVO, TREVO 2, MR Rescue). The benefit-to-risk ratio (BRR) was estimated separately for each study using the following formula: BRR= (% of 3-month mRS of 0-1/ % of 3-month mRS of 6) x (median baseline NIHSS of study of interest/median baseline NIHSS of all evaluated studies). Results: The BRRs of all analyzed studies (median pre-treatment NIHSS 17 points) plotted against time to intervention are shown in Figure. The BRRs ranged from 0.31 in the MR Rescue endovascular arm to 5.80 in the high-dose of tenecteplase in TAAIS. The most effective RPTs were: IVT with tenecteplase in TAAIS (BRR 5.80), sonothrombolysis (BRR 2.75), followed by IVT with alteplase in SYNTHESIS expansion trial (BRR 2.68). The endovascular arm of TREVO had the highest BRR (1.70) among the acute thrombectomy studies evaluating different devices. BRR strongly correlated with time to treatment from symptom onset (R2:0.640; p<0.0001) Conclusions: IVT with a novel agent followed by sonothrombolysis appear to be associated with the highest BRR. Almost two thirds of the variation of BRR can be explained by differences in onset-to-treatment time between studies indicating a strong time-dependency of BRR in acute RPT.