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Introduction: The aim of the present systematic review and meta-analysis was to evaluate the safety and efficacy of intravenous thrombolysis with tissue plasminogen activator (tPA) delivered through telestroke networks in patients with acute cerebral ischemia.Methods: We conducted a systematic review and meta-analysis according to PRISMA guidelines of all available randomized controlled and prospective non-randomized studies that compared telemedicine-guided thrombolysis to either phone-guided or on-site thrombolysis. Outcomes of interest were mortality and favorable functional outcome (i.e., modified Rankin scale 0-1) at 90-days and any tPA-associated intracerebral hemorrhage. Fixed-effect model was used to compute pooled effect estimates and the I2 statistic was used to assess heterogeneity.Results: Of 529 records identified through database searching, only five studies with a total of 1,562 patients fulfilled our eligibility criteria. Intracerebral hemorrhage rates were similar between patients subjected to telemedicine-guided thrombolysis and those receiving tPA after phone consultation or on-site at a stroke center (odds ratio=0.68, 95%CI: 0.36-1.26; p=0.216) with no evidence of heterogeneity (I2=0%). Neither there was a difference in mortality (odds ratio=1.17, 95%CI: 0.85-1.61; p=0.328) nor in favorable functional outcome (odds ratio=1.24, 95%CI: 0.83-1.86; p=0.291) at 90-days between telemedicine-guided thrombolysis and phone-guided or on-site thrombolysis. There was evidence of low heterogeneity (I2=29% and 37%, respectively; p>0.1). No evidence of publication bias (p>0.1, Egger statistical test) was detected.Conclusions: Our findings indicate that intravenous tPA delivery through telestroke networks is safe and effective. Lack of prospective trials, however, emphasize the need to further substantiate these findings in studies with sound methodological quality.