OBJECTIVE : To evaluate the safety of acute ischemic stroke (AIS) therapy in patients with infective endocarditis (IE) with intravenous thrombolysis (IVT) or endovascular therapy (EVT) such as mechanical thrombectomy. METHODS : We conducted a retrospective study of patients who underwent AIS therapy with IVT or EVT at a tertiary referral center from 2013 to 2017, that were later diagnosed with acute IE as the causative mechanism. We then performed a systematic review of reports of acute ischemic reperfusion therapy in IE since 1995 for their success rates in terms of neurological outcome, and mortality, and their risk of hemorrhagic complication. RESULTS : In the retrospective portion, 8 participants met criteria, of whom 4 received IVT and 4 received EVT. Through systematic review, 24 publications of 32 participants met criteria. Combined, a total of 40 participants were analyzed: 18 received IVT alone, 1 received combined IVT plus EVT, and 21 received EVT alone. IVT compared to EVT were similar in rates of good neurologic outcomes (58% versus 76%, P= .22) and mortality (21% versus 19%, P= .87), but had higher post-therapy intracranial hemorrhage (63% versus 18% [P= .006]). CONCLUSIONS : IV thrombolysis has a higher rate of post-therapy intracranial hemorrhage compared to EVT. EVT should be considered as first-line AIS therapy for patients with known, or suspected, IE who present with a large vessel occlusion.