Regadenoson (REG) is a A2a receptor selective pharmacologic SPECT imaging agent. Its safety in unselected chronic obstructive pulmonary disease (COPD) or asthma (AM) undergoing SPECT imaging has not been well evaluated. We retrospectively identified 228 patients (COPD n = 126 and AM n = 102, Grp 1) undergoing REG SPECT from Jan to Nov 2009 and compared to 1,142 patients without COPD and AM (control, Grp 2). A standard 400 μg REG bolus was used and gated Tc-99 m tetrofosmin SPECT done. Patient demographics, REG SPECT data, side effects, arrhythmia occurrences, and any exacerbation of COPD or AM leading to treatment, hospitalization or death were evaluated. The side effect profile of Grp 1 was also compared to a historical cohort who underwent intravenous dipyridamole thallium-201 imaging and adenosine SPECT. Both groups were comparable with regards to baseline characteristics. There was 0% incidence of clinical exacerbation of COPD or AM after REG. COPD patients had more non-significant arrhythmias (58.3% vs. Grp 2, 43%, P = 0.004). There was 0% incidence of any atrio-ventricular block and only 2 instances of brief supraventricular tachycardia. When compared to the historical cohort of COPD who underwent IV dipyridamole thallium imaging, COPD in Grp 1, had more dyspnea and flushing and when compared to COPD/AM patients who underwent adenosine SPECT, Grp 1 pts had more of flushing and headache (24.9% vs. 2.8%, P = <0.001) but less of bronchospasm (1.3% vs. 6.9%, P = 0.022) and AV block (0% vs. 4.2%, P = 0.014). REG SPECT can be safely performed in COPD and AM population.