Adenosine infusion, as is used in stress single photon-emission computed tomographic (SPECT) imaging, produces an increase in heart rate (HR) and a decrease in blood pressure (BP). The increase in HR is most likely due to direct sympathetic stimulation rather than a reflex to the decrease in BP. In this study, it was hypothesized that the HR response to adenosine is different in patients with versus without diabetes mellitus (DM) in the setting of normal SPECT imaging results. We studied 60 patients with DM (53% women, mean age 62 ± 10 years) and 60 controls (50% women, mean age 61 ± 12 years) (p = NS). All patients underwent adenosine SPECT imaging (140 μg/kg/min for 5 minutes) for clinical indications and had normal perfusion and systolic left ventricular function. HR and BP were measured at baseline and during adenosine infusion. HR ratio was defined as peak HR divided by baseline HR and the change as peak HR minus baseline HR. The change in HR (17 ± 12 vs 22 ± 14 beats/min, p = 0.034) and the ratio (1.24 ± 0.20 vs 1.33 ± 0.25, p = 0.048) were significantly lower in patients with DM compared with those without DM. The baseline and change in mean BP were not significantly different between the 2 groups. In a stepwise regression analysis model, DM was identified as a predictor of the change in HR (p = 0.022). In conclusion, HR response to adenosine infusion is diminished in patients with DM with normal SPECT imaging results. This is likely due to cardiovascular autonomic neuropathy and may carry important prognostic information. © 2008 Elsevier Inc. All rights reserved.