Introduction: Little is known about the impact of the total cavopulmonary connection (TCPC) on resting and exercise hemodynamics in a single ventricle (SV) circulation. The aim of this study was to elucidate this mechanism using a lumped parameter model of the SV circulation. Methods: Pulmonary vascular resistance (1.96 ± 0.80 WU) and systemic vascular resistances (18.4 ± 7.2 WU) were obtained from catheterization data on 40 patients with a TCPC. TCPC resistances (0.39 ± 0.26 WU) were established using computational fluid dynamic simulations conducted on anatomically accurate 3D models reconstructed from CMR (n=16). These parameters were used in a lumped parameter model of the SV circulation to investigate the impact of TCPC resistance on SV hemodynamics under resting and exercise conditions. A biventricular model was used for comparison. Results: For a biventricular circulation, the cardiac output (CO) dependence on TCPC resistance was negligible (sensitivity = -0.064 L/Min/WU), but not for the SV circulation (sensitivity = -0.88 L/Min/WU). Capacity to increase CO with heart rate was also severely reduced for the SV. At a simulated heart rate of 150 beats per minute, the SV patient with the highest resistance (1.08 WU) had a significantly lower increase in cardiac output (20.5%) when compared to an SV patient with the lowest resistance (50%) and the normal circulation (119%). This was due to the increased afterload (+35%) and decreased preload (-12%) associated with the SV circulation. Conclusion: TCPC resistance has a significant impact on the resting hemodynamics and exercise capacity of patients with an SV physiology.