Background— For patients identified before hospital arrival with ST-segment–elevation myocardial infarction, bypassing the emergency department (ED) with direct transport to the catheterization laboratory may shorten reperfusion times. Methods and Results— We studied 12 581 ST-segment–elevation myocardial infarction patients identified with a prehospital ECG treated at 371 primary percutaneous coronary intervention–capable US hospitals participating in the Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With The Guidelines, including those participating in the American Heart Association Mission: Lifeline program from 2008 to 2011. Reperfusion times with primary percutaneous coronary intervention and in-hospital mortality rates were compared between patients undergoing ED evaluation and those bypassing the ED. ED bypass occurred in 1316 patients (10.5%). These patients had a lower frequency of heart failure and shock on presentation and nonsystem reasons for delay in percutaneous coronary intervention. ED bypass occurred more frequently during working hours compared with off-hours (18.3% versus 4.3%); ED bypass rate varied significantly across hospitals (median, 3.3%; range, 0%–71%). First medical contact to device activation time was shorter (median, 68 minutes [interquartile range, 54–85 minutes] versus 88 minutes [interquartile range, 73–106 minutes]; P <0.0001) and achieved within 90 minutes more frequently (80.7% versus 53.7%; P <0.0001) with ED bypass. The unadjusted in-hospital mortality rate was lower among ED bypass patients (2.7% versus 4.1%; P =0.01), but the adjusted mortality risk was similar (adjusted odds ratio, 0.69; 95% confidence interval, 0.45–1.03; P =0.07). Conclusions— Among ST-segment–elevation myocardial infarction patients identified with a prehospital ECG, the rate of ED bypass varied significantly across US hospitals, but ED bypass occurred infrequently and was mostly isolated to working hours. Because ED bypass was associated with shorter reperfusion times and numerically lower mortality rates, further exploration of and advocacy for the implementation of this process appear warranted.