Background: Sickle cell anemia is an autosomal recessive inherited disorder that affects approximately 5% of the world population. These patients are at greater risk for developing Hodgkin’s lymphoma. Cardiopulmonary bypass can trigger lethal vaso-occlusive crises in those patients if they are subjected to hypoxia, hypothermia, acidosis, or low-flow states. Case presentation: This case report describes a patient with sickle cell anemia and history of stroke was diagnosed with Bicuspid aortic valve stenosis and aneurysmal dilatation of the ascending aorta complicated with infective endocarditis. During routine workup he was discovered to have Hodgkin’s Lymphoma. He successfully underwent mechanical aortic valve and aortic root replacement. He underwent exchange transfusion preoperatively and one time immediately before initiating of Cardiopulmonary bypass. There was no major vaso-occlusive crisis occurred throughout the surgery. Patient was discharged in stable condition, and was scheduled for involved site radiation therapy for Hodgkin’s Lymphoma management. Conclusion: Sickle Cell Disease can be very challenging during cardiopulmonary bypass. Exchange transfusion can reduce HbS, and increase hematocrit level. Mild hypothermia can be used if sufficient CPB flows and venous saturation are maintained.