Prostacyclin (PGI 2), a newly discovered short-acting prostaglandin that inhibits platelet aggregation, was evaluated as an agent for prevention of cardiopulmonary bypass–induced thrombocytopenia. Ten adult, splenectomized greyhounds were divided into three treatment groups prior to beginning 120 minutes of partial cardiopulmonary bypass. Group 1 animals received 300 units of heparin per kilogram of body weight, Group 2 animals received 300 units of heparin per kilogram plus PGI 2, 1.5 μg per minute, and Group 3 animals received 300 units of heparin per kilogram plus PGI 2 3.0 μg per minute. Bypass and PGI 2 infusion were started simultaneously. Mean platelet counts of each group at 5 minutes were approximately 40% of prebypass levels. Additional platelet loss was seen in Groups 1 and 2 at 30, 60, and 120 minutes. However in Group 3, platelet counts at 30 and 60 minutes were essentially unchanged from prebypass levels. At 30, 60, and 120 minutes of cardiopulmonary bypass, the differences between Groups 1 and 3, and 2 and 3 are highly significant ( p < 0.01). We conclude that PGI 2 is an effective agent for preserving platelet levels during experimental cardiopulmonary bypass. Furthermore, it is possible that platelet loss during cardiopulmonary bypass may be caused, in part, by an imbalance between PGI 2 and thromboxane A 2, which results in excessive platelet adhesion and aggregation.