Background: The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study demonstrated a low 5-year hard cardiac event rate. We hypothesized that a blunted heart rate response (HRR, maximum percent change) to adenosine, a simple marker of cardiac autonomic neuropathy, will identify a cohort at higher cardiac risk. Methods: In DIAD, 518 participants were randomized to screening adenosine myocardial perfusion imaging (MPI) and had available data. HRR < 20% was considered abnormal. The primary endpoint was a composite of nonfatal myocardial infarction and cardiac death. Results: During 4.7 ± 0.9 years of follow-up 15 (3%) participants experienced the primary outcome. Participants with lower HRR experienced more events than those with higher HRR (8%, 3%, 1%, for HRR < 20% (n = 79), 20-39% (n = 182) and ≥ 40% (n = 257), respectively, p = 0.01). In a Cox proportional regression model that included MPI abnormalities and HRR, both were independently associated with cardiac events (p for model < 0.001). HRR < 20% was associated with 9-fold increased risk (p = 0.007) and moderate/large abnormal MPI was associated with 6-fold increased risk (p = 0.004). Participants with both abnormal MPI and HRR (n = 8) were at highest risk for cardiac events (38%) whereas those with HRR ≥ 40%, irrespective of MPI abnormalities (n = 234), were at extremely low risk (≤ 1%, log-rank p < 0.001). Conclusions: In DIAD, abnormal HRR to adenosine infusion is an independent predictor of cardiac events. This easily obtained marker of cardiac autonomic neuropathy identifies asymptomatic patients with type 2 diabetes mellitus at increased risk, particularly when associated with abnormal MPI, who may warrant further testing and more aggressive cardiovascular risk factor management. © 2012 Elsevier Ireland Ltd.