An 18 year old girl, with acute myeloid leukemia, developed progressive hemolysis after receiving multiple transfusions with ABO-incompatible platelets. It was caused by passive transfusion of anti-A and -B isoagglutinin from the donor plasma. Her hemoglobin level returned to normal after giving group compatible or pooled and reduced volume platelet concentrates. Transfusing group-incompatible platelets is not contraindicated, but donor plasma reduction should be considered for those patients who need prolonged platelet support. Testing for isoagglutinin titer in group O donors is an alternate method to reduce the incidence of plasma-induced hemolysis in group-incompatible platelet transfusions.