The Fontan procedure provides relief from cyanosis in patients with univentricular hearts. A major clinical unmet need is to understand whether the venous flow patterns of the Fontan circulation lead to the development of congestive hepatopathy and other life-threatening complications. Currently, there is no consensus on whether heart beat or respiration is the main driving force of venous return and which one affects the periodic flow changes for the most (i. e., pulsatility). The present study, for the first time, quantified respiratory and cardiac components of the venous flow in the inferior vena cava (IVC) of 14 Fontan patients and 11 normal controls using a novel approach ("physio-matrix"). We found that in contrast to the normal controls, respiration in Fontan patients had a significant effect on venous flow pulsatility, and the ratio of respiration-dependent to the cardiac-dependent pulsatility was positively associated with the retrograde flow. Nevertheless, the main driving force of net IVC flow was the heart beat and not respiration. The separate analysis of the effects of respiration and heart beat provides new insights into the abnormal venous return patterns that may be responsible for adverse effects on liver and bowel of the patients with Fontan circulation.