Background: Pulse pressure variation (PPV) is based on heart-lung interaction and its association with the imbalance between pulmonary and systemic blood flow (Qp:Qs) has been understudied. We hypothesized that (1) baseline PPV (after induction of anesthesia) is different in a mixed congenital heart disease population with different Qp:Qs, (2) baseline PPV is different between a pooled group with high Qp:Qs and one with low Qp:Qs, and (3) a systemic-pulmonary shunt procedure results in reduced PPV compared to baseline. Methods: We retrospectively reviewed the medical charts of children who presented to the operating room for cardiac surgery between 2010 and 2018. General patient characteristics, PPV, and other hemodynamic parameters following the induction of general anesthesia were retrieved. Patients were grouped according to the type of congenital heart disease, and whether the Qp:Qs ratio was higher or lower than 1. We also identified patients who received a systemic-pulmonary shunt in order to evaluate changes in PPV. Results: A total of 1253 patients were included in the study. Baseline PPV differed significantly according to the type of congenital heart disease, with atrial septal defect showing the lowest PPV (9.5 \pm 5.6%) and tricuspid valve malformation the highest (21.8 \pm 14.1%). The high Qp:Qs group (n = 932) had significantly lower PPV compared to the low Qp:Qs group (n = 321; 11.8 \pm 5.7% vs. 14.9 \pm 7.9%, respectively; p 0.001). PPV decreased significantly following systemic-pulmonary shunt. Conclusions: PPV was associated with Qp:Qs imbalance in children undergoing general anesthesia for cardiac surgery. A lower PPV was associated with increased Qp:Qs. Clinicians should take this into account when using PPV to evaluate volume status and when conducting clinical trials in a mixed population of patients with congenital heart disease.