The recommended treatment for ST-segment elevation myocardial infarction (STEMI) is primary percutaneous coronary intervention (pPCI). However, in a non-negligible proportion of patients, pPCI is ineffective and the cardiologist must face the decision of how to achieve optimal myocardial reperfusion. Although the possibility of a rescue fibrinolytic strategy has not been evaluated yet in this clinical setting, it is a viable alternative to emergency cardiac surgery. We here report the case of a 60-year-old STEMI patient presenting with a coronary anatomy unsuitable for percutaneous mechanical revascularization, characterized by marked dilation and tortuosity of the proximal and middle epicardial segments. After pPCI failure, the administration of recombinant tissue-type plasminogen activator allowed us to obtain reperfusion as shown by clinical outcome, ST-segment resolution and subsequent angiographic study. No indication was given to further percutaneous or surgical revascularization. The long-term pharmacological management of these patients represents a challenge for the clinician, also considering the available data on the use of new antiplatelet and anticoagulant molecules and their possible associations.