Cardiopulmonary bypass (CPB) in children is associated with a capillary leak due to inflammatory response, which results in an increase in total body water. This study was designed to reveal that our miniaturized CPB system reduced the peri-operative systemic inflammatory response in small infants. In our institution, the priming volume has been reduced from 500 ml to 140 ml currently. Eighty consecutive patients weighing <5 kg were retrospectively reviewed. The postoperative peak C-reactive protein (CRP), body weight gain (%BWG), and the duration of postoperative mechanical ventilation (MVT) data were collected for each patient. Stepwise multiple logistic regression analyses were used to investigate which of the factors most affected the peri-operative inflammatory responses. A priming volume (coefficient: 0.060, P=0.01), most affected the postoperative peak CRP (mg/dl). A combination of priming volume (coefficient: 0.015, P=0.006), and bypass time (coefficient: 0.013, P=0.028), most affected %BWG (%). A combination of priming volume (coefficient: 0.05, P=0.001) and age (coefficient: -0.02, P=0.001) most affected the MVT (days). The miniaturized circuits reduced the peri-operative inflammatory response, resulting in reduced postoperative systemic edema, and postoperative mechanical ventilation time.