OBJECTIVE - Elevated heart rate has been predictive of cardiovascular disease and has been proposed as a global index of the autonomic nervous system influence on the heart. Hyperinsulinism has been shown to trigger sympathetic activity experimentally; however, the clinical and epidemiological data on the association of heart rate with hyperinsulinism and insulin resistance are conflicting. RESEARCH DESIGN AND METHODS- Insulin sensitivity (S-I) and the acute insulin response (AIR) to glucose were assessed by a frequently sampled intravenous glucose tolerance test and related to resting heart rate in the tri-ethnic nondiabetic population (n = 1,000) of the Insulin Resistance Atherosclerosis Study. RESULTS - Heart rate was related to fasting insulin (r = 0.20), intact proinsulin (r = 0.15), split proinsulin (r = 0.17), and AIR (r = 0.18), and an inverse relation was found between heart rate and S-I (r = -0.19) tall P values <0.0001, adjusted for age, sex, ethnicity glucose tolerance status, and smoking). In a multiple linear regression analysis (adjusting for age, sex, ethnicity, clinical center, glucose tolerance status, and smoking), heart rate was significantly and independently associated with AIR, proinsulin, and S-I. CONCLUSIONS - Proinsulin, acute insulin secretion, and S, are associated with heart rate in nondiabetic subjects.