OBJECTIVE To determine the efficacy of decreasing cardiopulmonary bypass (CPB) prime volume for neonates and small infants by using low prime oxygenators, small diameter polyvinyl chloride (PVC) tubing and removing the arterial line filter (ALF) in an effort to reduce intraoperative exposure to multiple units of packed red blood cells (PRBC). METHODS Two retrospective database studies comparing neonatal CPB prime volume were undertaken: Study 1--A CPB circuit consisting of a 1/8 inch arterial line, a 3/16 inch venous line and a low prime oxygenator with 172 ml total circuit prime (n=74) was compared to a circuit with a 3/16 inch arterial line, a 1/4 inch venous line and a higher prime oxygenator with a 350 ml total circuit prime (n=74). Study 2--The 172 ml circuit (n=389) was compared to a circuit that included an ALF and had a total circuit prime volume of 218 ml (n=389). RESULTS Study 1--of the 74 neonates and small infants whose CPB prime volume was 350 ml, 19 were exposed to two or more intraoperative exogenous PRBC units while only 3 neonates and small infants in the 172 ml prime group (n=74) received two or more units (p = 0.0002). Study 2--of the 389 neonates and small infants where an ALF was used (prime volume 218 ml), 54 were exposed to two or more exogenous PRBC units while only 36 of the 389 patients where an ALF was not used (prime volume 172 ml) received two or more units of intraoperative PRBCs (p = 0.0436). CONCLUSION Decreasing the neonatal and small infant extracorporeal circuit prime volume by as little as 46 ml resulted in significantly fewer multiple exposures to exogenous PRBC units.