Hemolysis can occur as a consequence of extracorporeal membrane oxygenation (ECMO) and is associated with increased mortality and morbidity. Shear stress generated by flow through the circuit and oxygenator is believed to cause ECMO-induced hemolysis. We hypothesize that either a smaller dimension oxygenator or an in-line hemofilter will increase ECMO-associated hemolysis. Circuits were configured with a Quadrox-D Adult oxygenator (surface area 1.8 m), Quadrox-iD Pediatric oxygenator (surface area 0.8 m), or Quadrox-D Adult oxygenator with an in-line hemofilter (N = 4) and ran for 6 hours. Samples were collected hourly from the ECMO circuit and a time-based hemolysis control. Plasma hemoglobin levels were assayed. Circuit-induced hemolysis at each time point was defined as the change in plasma hemoglobin standardized to the time-based hemolysis control. Plasma hemoglobin increased with the use of the smaller dimension pediatric oxygenator as compared with the adult oxygenator when controlling for ECMO run time (p = 0.02). Furthermore, there was a greater pressure gradient with the smaller dimension pediatric oxygenator (p < 0.05). Plasma hemoglobin did not change with the addition of the in-line hemofilter. The use of a smaller dimension pediatric oxygenator resulted in greater hemolysis and a higher pressure gradient. This may indicate that the increased shear forces augment ECMO-induced hemolysis.