Randomized clinical trials (RCTs) usually enroll selected patient populations that may not be representative for patients seen in everyday practice. Therefore, concerns have been raised regarding their external validity. For the present study we evaluated the MITRA Plus registry and included 20,175 patients with ST-elevation myocardial infarction. We defined RCT-ineligible patients as patients fulfilling >or=1 of the following criteria: age >or=75 years, prehospital delay >12 hours, prehospital cardiopulmonary resuscitation, cardiogenic shock, impaired renal function, and previous stroke. Those patients (n = 9,369, 46.4%) were compared to patients eligible for enrollment in RCTs (n = 11,806, 53.6%). Ineligible patients were older (p <0.0001), more often were women (p <0.0001), and more often had concomitant diseases (p <0.0001). Ineligible patients less often received early reperfusion therapy (p <0.0001), aspirin (p <0.0001), clopidogrel (p <0.0001), and statins (p <0.0001). Ineligible patients had a higher hospital mortality (20.1% vs 4.9%; p <0.0001) and a higher rate of nonfatal strokes (1.5% vs 0.4%, p <0.0001) compared to eligible patients. Early reperfusion therapy (thrombolysis and/or percutaneous coronary intervention [PCI]) in ineligible patients was associated with a significant decrease of hospital mortality (odds ratio 0.62, 95% confidence interval 0.49 to 0.79), with primary PCI being more effective than thrombolytic therapy (odds ratio 0.52, 95% confidence interval 0.41 to 0.65). In conclusion, about 50% of patients with ST-elevation myocardial infarction seen in clinical practice are usually excluded from RCTs. Hospital mortality in those patients is very high. Primary PCI improves the prognosis and is therefore the preferred reperfusion strategy in these patients.