Cold autoantibodies are targeted against “self” antigens on the red cell surface, and react best at temperatures well below body temperature (contrast to warm autoantibodies). Cold autoantibodies commonly target antigens in the I system (I or i), and they are really, really, REALLY common! Fortunately, they are also really benign in most people. Occasionally, cold autoantibodies can react in warmer temperatures (i.e., they may have a broad “thermal amplitude“) and can destroy red cells in “cold autoimmune hemolytic anemia.” This is classically seen in association with Mycoplasma pneumonia infection (auto-anti-I) or infectious mononucleosis (auto-anti-i); students would be wise to remember those associations.