Background and Purpose— The safety of IV r-tPA (intravenous tissue-type plasminogen activator) for acute ischemic stroke (AIS) treatment after recent myocardial infarction (MI) is still a matter of debate. We studied the safety of delivering IV r-tPA to AIS patients with a MI within the preceding 3 months. Methods— Retrospective review of consecutive AIS admitted to 2 tertiary university hospitals’ and systematic literature review for AIS patients with history of MI in the previous 3 months. Patients were divided into 2 groups: treated or not treated with standard IV r-tPA dose for AIS. Cardiac complications (cardiac rupture/tamponade, intracardiac thrombus embolization, or life-threatening arrhythmias) were compared between groups and assessed by type of MI (non–ST-segment–elevation myocardial infarction [STEMI], or STEMI) and time elapsed between vascular events. Results— One hundred and two patients were included; 46 (45.1%) were derived from literature review. Median age (interquartile range) was 64 (53–75) years old, and 69 (67.6%) were men. Forty-seven (46.1%) received IV r-tPA. In the treated group, 25 (53.2%) and 23 (48.9%) patients had, respectively, concurrent AIS and MI and STEMI, in comparison with 12 (21.8%; P =0.002) and 36 (65.5%; P =0.110) patients in the nontreated. Four (8.5%) IV r-tPA–treated patients died from confirmed or presumed cardiac rupture/ tamponade, all with a STEMI in the week preceding stroke. This complication occurred in 1 (1.8%) patients in the nontreated group ( P =0.178). There were no differences in thrombus embolization (1 [2.1%) versus 2 [3.6]; P =1.000) and life-threatening arrhythmias (3 [6.4%) versus 7 [12.7]; P =0.335). No non-STEMI patients receiving IV r-tPA had cardiac complications. Conclusions— In patients with AIS and recent or concurrent MI, MI type and the time elapsed between the 2 events should be taken into consideration when deciding to deliver IV r-tPA. Although recent non-STEMI or concurrent events seem safe, STEMI in the week preceding stroke should prompt caution. The low number of events and publication bias may have influenced our conclusions.