This chapter embarks on an in-depth examination of the unique challenges and essential considerations for performing successful cardiac surgery, specifically cardiopulmonary bypass, on Jehovah’s Witness patients. Owing to their specific interpretation of Biblical passages, Jehovah’s Witness patients not only decline blood transfusions but also forbid the re-transfusion of their own autologous blood once separated from their circulatory system, thus presenting a unique challenge to the cardiac surgery team. This chapter underscores the importance of detailed preoperative discussions regarding acceptable blood products, preoperative optimization, blood conservation strategies, and contingency plans. A multidisciplinary approach is emphasized, advocating for comprehensive patient education on the surgery’s potential risks and benefits. Blood conservation strategies, encompassing preoperative supplementation, hemodilution, intraoperative blood salvage, meticulous pump management, the use of antifibrinolytics, and the reduction of laboratory draws, are explored in detail. This chapter serves as a focused guide for the cardiac surgery team, aiming to effectively manage the unique needs of Jehovah’s Witness patients during cardiopulmonary bypass, while respecting their deeply held religious beliefs.