Rate of spontaneous depolarization in the sino-atrial node (SAN) is modulated by sympathetic and parasympathetic neural inputs. These interactions manifest as variations in instantaneous heart rate, commonly referred to as heart rate variability (HRV). Mathematical models of HRV should therefore be based on effects of the autonomic nervous system on ion channel kinetics responsible for SAN automaticity. We describe a model of HRV based on the above interactions. Generation of pace maker potential was simulated using an ‘integrate and fire’ model, analogous to the charging of a capacitor via a resistor, starting from a resting membrane potential (RMP) of -50 mV to a reversal potential of -15 mV. When the potential reaches a threshold of -40 mV, the action potential is triggered. Two specific enhancements were made to the above basic model. Firstly, Phase 4 depolarization was assumed to occur in two stages: an initial slow exponential rise followed by a second accelerated exponential rise [associated with voltage independent late diastolic spontaneous Ca2+ release (1)]. Secondly, time constants for membrane depolarization at successive epochs were the product of linear interactions between (a) inherent stochasticity in channel activity and (b) sinusoidal inputs from the sympathetic (0.1Hz) and parasympathetic (0.25Hz) efferents that increased and decreased the open probability of ion channels respectively. Average heart-rate (beats per minute) and variability (standard deviation as a percentage of mean heart rate) at varying levels of input from the sympathetic and parasympathetic systems are shown in Table 1. Maximal variability was seen when depolarization occured under both sympathetic and parasympathetic control (SD=34%). Variability was considerably lower when only one of the autonomic components was active (17%) and lowest when the heart was completely isolated from the autonomic inputs (0.1%). We provide the first comprehensive model of HRV based on interactions between SAN ion channels and autonomic nerves. This model acknowledges two well recognized but, hitherto unexplained, features of HRV: namely (1) Low levels of HRV can be demonstrated in the absence of autonomic inputs (e.g isolated heart preparations); and (2) HRV is reduced during both sympathetic blockade (2) and sympathetic stimulation (3).