© 2015, American Society of Nuclear Cardiology. Background: Regadenoson (REGA), a selective adenosine A2A receptor agonist, is the most widely used stress agent for SPECT myocardial perfusion imaging (MPI) in the United States. The diagnostic accuracy of REGA MPI is comparable to Adenosine MPI, but its prognostic value is not well defined. Methods: We categorized 1,400 patients (700 consecutive normal and 700 consecutive abnormal REGA-MPIs) into 4 groups based on the perfusion defect size using automated quantitative analysis: Group 1: normal perfusion; Group 2: <10% of left ventricle; Group 3: 10%-20%; Group 4: >20%. The primary outcome was a composite of cardiac death, myocardial infarction (MI), and late coronary revascularization (CR >90 days after MPI). Results: Of the 1,400 patients (42% male, 37% diabetes, 21% heart failure, 26% end-stage renal disease), the primary outcome occurred in 23% (17% cardiac death, 4% MI, 6% late CR) during 46 ± 18 months of follow-up and 8% had early CR (within 90 days of MPI). Early CR occurred in 0.4%, 9%, 17%, and 17% and the primary outcome in 10%, 27%, 31%, and 43% in Groups 1-4, respectively (P < .001 for both). In an adjusted Cox proportional model, the hazard ratio for the primary outcome was 2.68 (1.77-4.06), 3.32 (2.28-4.83), and 4.05 (2.78-5.91) for Groups 2-4 compared to Group 1. Conclusion: REGA MPI provides powerful prognostic information that has important implications in patient management and can guide clinical practice.