AIMS: To examine the extent and impact on clinical outcomes of adherence to electrocardiogram (ECG) entry criteria in ST-elevation myocardial infarction patients in the assessment of pexelizumab in acute myocardial infarction (APEX-AMI) trial. METHODS AND RESULTS: We examined the frequency, characteristics, and outcomes of patients enrolled in APEX-AMI trial who did not meet the trial ECG entry criteria. Among 5615 patients analysed, 28.8% did not meet ECG entry criteria: this occurred more than twice as frequently amongst those with high-risk inferior vs. those with other MI (42.3 vs. 19.3%, P < 0.001). Regardless of infarct location, patients who failed to meet ECG entry criteria had significantly lower mortality (2.5 vs. 4.5% at 30 days and 3.1 vs. 5.3% at 90 days; both P < 0.001) and the composite rate of death, cardiogenic shock, or CHF (5.8 vs. 10.3% at 30 days and 6.9 vs. 11.4% at 90 days; both P < 0.001) as compared to those who met criteria. CONCLUSION: In APEX-AMI over one-quarter of enrolled patients did not meet ECG entry criteria and had better outcomes than eligible patients. Although the trial's primary result was unaffected by alignment with the baseline ECG criteria, our findings may have important implications in designing future trials.