A large-animal model is essential for the assessment of functional parameters in cardiovascular surgical research. To date the canine model has been used successfully because of its availability and tolerance to cardiopulmonary bypass. However, because of decreased availability and increased cost, an alternative animal model is now needed. The swine model has been used in experimental cardiac procedures, but complications during cardiopulmonary bypass have presented a formidable challenge. These complications include enormous fluid shifts from the vascular bed, increased metabolic acidosis, and marked hemoglobinuria. To eliminate these deleterious complications within the swine model, a number of technical alterations were achieved. The priming solution used for the extracorporeal circuit was altered to consist of 1000 mL lactated Ringer's solution. 500 mL 20% mannitol, 500 mL 6% dextran in 5% detrose solution. 50 mEq sodium bicarbonate, and 10,000 IU heparin. The extracorporeal circuit employed the use of membrane oxygenation. Three different blood flow rates (150, 175, and 200 mL/kg min-1) were studied. We conclude that the optimum blood flow rate for cardiopulmonary bypass in swine is in the range of 175-200 mL/kg min-1. Membrane oxygenation results in less damage to blood during cardiopulmonary bypass. The asanguinous hyperosmolar priming solution is beneficial for cardiopulmonary bypass in swine to greatly reduce fluid shifts, prevent metabolic acidosis, and eliminate hemoglobinuria.