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. 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 three-dimensional models reconstructed from MRI (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. For a biventricular circulation, the cardiac output (CO) dependence on TCPC resistance was negligible (sensitivity=-0.064 l.min(-1).WU(-1)) but not for the SV circulation (sensitivity=-0.88 l.min(-1).WU(-1)). The capacity to increase CO with heart rate was also severely reduced for the SV. At a simulated heart rate of 150 beats/min, the SV patient with the highest resistance (1.08 WU) had a significantly lower increase in CO (20.5%) compared with the SV patient with the lowest resistance (50%) and normal circulation (119%). This was due to the increased afterload (+35%) and decreased preload (-12%) associated with the SV circulation. In conclusion, TCPC resistance has a significant impact on resting hemodynamics and the exercise capacity of patients with a SV physiology.