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Acute myocardial infarction (AMI) is uncommon in the acute phase of acute ischemic stroke (AIS) and occurs in approximately 1% of the population. Here, we report a paradoxical case of AMI during tissue plasminogen activator (t-PA) infusion for AIS. We review and analyze the previously reported cases. We found that only patients with AMI which occurred after thrombolytic therapy for AIS who received an adequate combination of anticoagulation plus percutaneous coronary intervention survived their events. Several mechanisms have been proposed for the development of AMI after thrombolytic therapy. These mechanisms include fragmented intra-cardiac thrombus, intensified platelet aggregation that may lead to an increased potential for intra-cardiac thrombus formation, and a reduction in clot-associated plasminogen that may lead to a paradoxical hypercoagulable state of the coronary arteries. Currently, there is no consensus regarding this specific scenario. We propose that the therapeutic benefit and the potential risk of hemorrhagic complications should be further investigated and individualized. In patients who receive thrombolytic therapy for AIS and who then develop post-thrombolytic AMI, we suggest that the maximum treatment for the subsequent AMI be instituted promptly to avoid short-term mortality.