Background: Adenosine and regadenoson increase heart rate (HR) when used as stress agents to produce coronary hyperemia due to direct sympathetic stimulation. We hypothesized that the HR response will be lower in patients with than in those without diabetes mellitus (DM). Methods: We studied the HR response (percentage maximal increase) in 2,000 patients in The ADenoscan Versus regAdenosoN Comparative Evaluation for Myocardial Perfusion Imaging (ADVANCE MPI 1 and 2) Trials with known DM status. Results: There were 643 patients with a history of DM (65.4 ± 0.4 years, 32% women) and 1,357 patients with no DM (65.5 ± 0.3 years, 29% women). Compared with non-DM, the DM group had higher HR at baseline (68.4 ± 0.48 vs 65.2 ± 0.31 beat/min, P < .001) and smaller HR response after adenosine or regadenoson administration (29.4% ± 0.64% vs 36.1% ± 0.54%, P < .001). Insulin therapy was associated with further blunting in the HR response (25.9% ± 1.0% vs 31.2% ± 0.8%, P < .001). After adjusting for β-blocker intake, baseline HR, age, gender, renal function, systolic blood pressure, and left ventricular systolic function, DM independently accounted for a decrease in the HR response. Conclusions: The HR response to adenosine and regadenoson in patients with DM is blunted. If additional studies confer an agreement between traditional tests for determination of autonomic neuropathy and this measure, then examination of HR response to these agents during myocardial perfusion imaging might add prognostic power. © 2009 Mosby, Inc. All rights reserved.