Progress in biomaterial technology and improvements in surgical and perfusion strategy ameliorated morbidity and mortality in pediatric cardiac surgery. In this study, we describe our clinical experience comparing performance of 2 neonatal oxygenators. From 01/2002 to 03/2011, 159 less than 5 kg body-weight babies underwent heart surgery. Ninety-four patients received a D901 Lilliput 1 oxygenator with standard bypass circuit (Group A), while 65 a D100 Kids with miniaturized bypass circuit (Group B). Miniaturization consisted in shortened arterial, venous, cardioplegia and pump-master lines. Priming composition consisted in ringer-acetate solution with addition of albumin and blood, with target Hct of 24% or greater. CPB was vacuum-assisted and started with empty venous line. MUF and Cell-Saver blood infusion was routinely applied. Average±SD age at repair was 37±38 in Group A and 59±60 days in Group B (p=0.005). Average±SD weight, height and BSA were 3.5±0.7 kg, 52±4 cm and 0.22±0.03 m2, respectively, in Group A, while 3.7±1 kg, 53±5 cm and 0.23±0.02 m2, respectively, in Group B (p=NS). Male sex was predominant (55% vs 58%, p=NS). Priming volume was 524±67 ml (Group A) and 337±53 ml (Group B) (p=0.001). There were no statistical differences in Hb at the start, during and at the end of CPB, but Group A required higher blood volume added to prime (111±33 vs 93±31 ml, p=0.001). In Group B, 2 surgical procedures were completed in total hemodilution. In Group B, CPB time and XCL time were shorter than in Group A (106±52 vs 142±78 min and 44±31 vs 64±31 min, respectively, p=0.001). There were 16 hospital deaths in Group A and 4 in Group B (p=0.04). Durations of mechanical ventilation and ICU stay were 5.3±3.2 vs 4.1±3.2 days (p=0.02) and 6.5±4.9 vs 5.1±3 days (p=0.03), respectively. There were significant differences in inotropic score (1083±1175 vs 682±938, p=0.04) and blood postoperative transfusion (153±226 vs 90±61 ml, p=0.04). Twenty-seven patients in Group A and 10 in Group B presented major adverse postoperative complications (p=0.04). Use of neonatal oxygenators with low priming volume, associated with miniaturized bypass circuit, seems to be a favourable strategy to decrease postoperative morbidity after cardiac surgery in neonates and infants.