MOTIVATION: The high frequency (HF) indices of heart rate variability (HRV), which reflect the magnitude of respiratory sinus arrhythmia (RSA), have been repeatedly used as measures of cardiac vagal tone. Recent studies, however, have shown experimentally that variations in these indices do not necessarily reflect proportional changes in cardiac parasympathetic outflow. OBJECTIVE: The goal of this study was to obtain a physiological-based theoretical evaluation of the relationship between RSA and cardiac vagal tone, which will help explain conflicting experimental results previously published. METHODS: We derived a theoretical model for heart rate (HR) response to gradual vagal blockade. The model implements the integral-pulse-frequency-modulation (IPFM) approach to sinoatrial (SA) node physiology. The level of vagal blockade was simulated by the addition of a cardio-selective muscarinic antagonist. RESULTS AND CONCLUSION: The derivations of the model lead to a closed set of equations, from which the dependence of the HF indices on the level of vagal blockade is deduced. It is shown that several aspects of the physiological condition may have a substantial effect on this relationship: the level of baseline vagal activity, the relationship between vagal tone and the fluctuations in its traffic, the level of sympathetic activity, etc em leader Hence, changes in the HF indices of HRV provide a plausible assessment of the changes in cardiac vagal tone only under a specific range of physiological conditions.