Perhaps the most important and widely studied blood group is the ABO blood group. It consists of antigens found on the outer surface of red cells and corresponding antibodies in plasma. The majority of the world's population (~80%) are 'secretors' which means that the antigens present in their blood will also be found in other body fluids such as saliva. An individual can be a Secretor (Se) or a non-secretor (se) and this is completely independent of whether the individual is of blood type A, B, AB, or O. From a very early age, the immune system develops antibodies against whichever ABO blood group antigens are not found on the individual's RBCs. Thus, a blood group A individual will have anti-B antibodies and a blood group B individual will have anti-A antibodies. Individuals with the most common blood group, O, will have both anti-A and anti-B in their plasma. Blood group AB is the least common, and these individuals will have neither anti-A nor anti-B in their plasma.

The primary structure of these antigens is an oligosaccharide precursor sequence on to which one or more sugars are attached at specific locations. The blood group oligosaccharide antigens A, B and H are produced by enzymes expressed by these genes and form the basis of the ABO 'blood type' phenotypes. A and B antigens were originally identified on red blood cells (RBCs) but later identified on other cell types and in bodily secretions. The ABO blood group system is important in blood transfusion, cell/tissue/organ transplantation and forensic evidence at crime scenes.

The H antigen is formed with the addition of a fucose sugar onto one of two precursor oligosaccharide sequences (Type 1 chains are Gal β1,3 GlcNAc β1,3 Gal R and Type 2 chains are Gal β1,4 GlcNAc β1,3 Gal R; where R is a glycoprotein (Type 1) or glycosphingolipid (Type 2). Type 2 chains are only found on RBCs, epithelial cells and endothelial cells. The H gene expressed in hematopoietic cells produces α-1,2-fucosyltransferase 1 (FUT1) which adds a fucose to Type 2 chains to form the H antigen in non-secretors. Type 1 chains are found in secretors. The Se gene expressed in secretory glands produces α-1,2-fucosyltransferase 2 (FUT2) which adds a fucose to Type 1 chains to form the H antigen in secretors.

The H antigen is abundant in individuals with blood group O and is the essential precursor for the production of A and B antigens. A and B antigens are formed by the action of glycosyltransferases encoded by functional alleles at the ABO genetic locus. The co dominant A allele encodes A transferase, which transfers an N acetylgalactosamine (GalNAc) sugar to the H antigen forming the A antigen. Similarly, the co dominant B allele encodes B transferase, which transfers a galactose (Gal) sugar to the H antigen forming the B antigen. Individuals who have both A and B alleles form the AB antigen. Individuals who are homozygous for the recessive O allele express the H antigen but do not form A or B antigens as they lack both the glycosyltransferase enzymes for their formation. Mutant alleles of the corresponding FUT1 or FUT2 genes result in either a H– phenotype (Bombay phenotype, Oh) or a weak H phenotype (para Bombay) where the affected individual cannot form H, A or B antigens (Kaneko et al. 1997, Koda et al. 1997). The biosyntheses of the A, B and H antigens are described in this section (Ewald & Sumner 2016, Scharberg et al. 2016).