This study examined the relation between heart rate (HR) response to adenosine and outcome in patients with end-stage renal disease (ESRD). The usual HR increase during adenosine infusion was caused by direct sympathetic stimulation. It was hypothesized that a blunted HR response, which was probably caused by sympathetic denervation, would be associated with a worse outcome in patients with ESRD. One hundred thirty-nine patients with ESRD being evaluated for renal transplantation who underwent coronary angiography and adenosine gated single-photon emission computed tomographic myocardial perfusion imaging were followed up for all-cause mortality. Percentage of change in HR (%ΔHR) was calculated as [(peak HR during adenosine infusion − HR at rest)/HR at rest] * 100. A control group of 54 patients (normal renal function and no diabetes) was included for comparison of HR responses. Mean age of patients was 54 ± 9 years, 30% were women, and 68% had type-2 diabetes mellitus. %ΔHR was 19.2 ± 18% in patients with ESRD versus 33 ± 25% in the control group (p <0.0001). At a mean follow-up of 3.4 ± 1.5 years, 50 patients (36%) with ESRD died. %ΔHR was lower in nonsurvivors than survivors (12.6 ± 14% vs 23 ± 19%; p = 0.0017). Patients with %ΔHR less than the median value were more likely to have lower left ventricular ejection fraction and larger end-diastolic volume (p <0.05 for each). In a multivariate logistic regression model, %ΔHR alone was an independent predictor of all-cause mortality (adjusted odds ratio 5.5, 95% confidence interval 2.3 to 12.9, p = 0.0001). In conclusion, patients with ESRD had a blunted HR response to adenosine, and degree of blunting was strongly associated with all-cause mortality.