BACKGROUND AND PURPOSE: We hypothesized that symptom improvement from enhanced external counterpulsation (EECP) is related to improved heart rate variability (HRV). METHODS: This prospective, multicenter study enrolled 27 patients with angina who underwent 48-hour ambulatory electrocardiogram monitoring at baseline, immediately after 35 hours of EECP, and at 1 month. Primary end points included change in time-domain (SD of normal-to-normal intervals) and frequency-domain HRV. RESULTS: Twenty-four patients completed the full course of EECP therapy and 3 ambulatory electrocardiograms. There were no significant changes in time-domain HRV measures after EECP. Patients younger than 65 years and those with heart failure had improved SD of normal-to-normal interval after EECP (P = .02). Although frequency-domain HRV measures did not change in the overall cohort, patients with diabetes had improved daytime low-frequency power (P = .016). CONCLUSIONS: There was no significant change in the time- or frequency-domain HRV measures after EECP. In diabetic individuals, there was an increase in low-frequency HRV, which has been associated with reduced mortality.