Changes in measures of heart rate variability (HRV) have been associated with an increased risk for sudden cardiac death. The mechanisms underlying this association are not known. The objective of this study was to assess the relationship between the amount of norepinephrine (NE) released from the cardiac sympathetic terminals and short-term HRV. The study comprised 8 healthy subjects, 12 patients with major depression, and 7 patients with panic disorder. Cardiac NE spillover was determined using direct coronary sinus blood sampling coupled with an NE isotope dilution methodology. Short-term HRV was quantified using detrended fluctuation analysis, symbolic dynamics, sample entropy, and standard time and frequency domain measures. Neither HRV nor cardiac NE spillover was significantly different between the analyzed groups. None of the standard HRV metrics was significantly correlated with cardiac NE spillover, but there was a moderate correlation between two complexity measures of HRV (symbolic dynamics) and cardiac NE spillover (patterns with 2 like variations, r = -0.37 and P = 0.05; and patterns with no variations: r = 0.34 and P = 0.06). In conclusion, there is no correlation between standard HRV measures and cardiac NE spillover in humans. Short-term complexity of heart rate is only moderately affected by sympathetic neural outflow. Therefore, the predictive value of most HRV measures for sudden cardiac death may predominantly result from their capacity to capture vagally mediated heart rate modulations.