Background and Purpose—Recombinant tissue plasminogen activator (rtPA; Actilyse) is not as widely used in clinical practice as it could be. Have new data since 1995 strengthened the evidence sufficiently to justify more widespread use of rtPA?Methods—We performed a sequential year-to-year cumulative meta-analysis of randomized controlled trials of rtPA in acute ischemic stroke.Results—Although the amount of data has doubled since 1995, effect estimates for key outcomes remain imprecise, and significant between-trial heterogeneity persists. In the most recent analysis, rtPA up to 6 hours after stroke yielded 55 fewer dead or dependent people per 1000 treated (95% CI, 18 to 92) despite some risk (nonsignificant excess of 19 deaths per 1000 patients treated; 95% CI, 6 fewer to 48 more). Severity of stroke, patient age, and aspirin use were possible sources of heterogeneity.Conclusions—Despite doubling of the data since 1995, the magnitude of risks and benefits with rtPA remains imprecise. This gap in knowledge may be hindering clinical use of rtPA and can be filled only by new trials designed to address these specific issues.