Intravenous immunoglobulin (IVIG) is made from thousands of donors having a variety of blood groups. All of the donors being used for IVIG production, with the exception of group AB donors, have in their plasma antibodies of variable titer commonly known as isohemagglutinins or ABO antibodies. As blood groups O and A are the most commonly found in the world population, most of the plasma used in IVIG production is from donors having these blood groups, with group B and group AB donors being fewer in number. Consequently, all batches of IVIG contain antibodies that are reactive with individuals of group A, group B, and group AB. These antibodies were originally discovered by Dr Karl Landsteiner in the early 1900s and are now known to consist of immunoglobulin (Ig)M, IgG, and IgA classes. As the process for producing IVIG results in almost exclusively IgG, isohemagglutinins contained in IVIG are of this immunoglobulin class. ABO antibodies are highly clinically significant and, because of this, blood bank cross-matching is done to ensure that blood of the correct type is transfused into recipients to avoid a so-called major mismatch or major incompatibility that can cause significant morbidity and often death. Administration of IVIG, which contains ABO antibodies, is often infused into individuals who have the corresponding ABO antigens, commonly called a minor mismatch, and although not as significant as a major mismatch, the isohemagglutinins contained in the IVIG have some risk for a significant transfusion reaction due to the ABO incompatibility. Indeed, currently there is no way to match IVIG to recipients according to blood type, so when IVIG is administered to group A, B, or AB recipients, there is potential for transfusion reactions analogous to a blood transfusion mismatch. For this reason, strict guidelines have been put into place to restrict the titers of the ABO antibodies contained in IVIG. This review will provide background information about the discovery and biochemistry of the ABO antigens and discuss the various isohemagglutinins that are found in plasma of the different ABO blood types and their potential clinical significance. In addition, a brief discussion of the controversial topic of the origins of these antibodies will conclude this review.