An ABO mismatch during transfusion can be lethal. Blood transfusion should be considered a form of organ transplantation – administering an ABO incompatible RBC transfusion can result in massive hemolysis, renal failure, respiratory failure and death. Due to this, LTOWB transfusion is always the safest option if the recipient’s blood type is unknown. Type O blood is the universal donor because the red blood cells (RBCs) do not express the A and B antigens to which the recipient might have naturally occurring hemolytic antibodies. While this CPG is not meant to make everyone a transfusion expert – understanding the basics on blood types and titers will help to ensure that this life-saving capability (blood transfusion) is implemented safely.