The first example of anti-Do^a, reactive with 64% of the Caucasian population, was reported by Swanson et al. in 1965. It was not until 1972 that Molthan et al. reported the antithetical antibody anti-Do^b. Thus, the Dombrock blood group system was defined and was estimated to be the fifth most useful blood group marker in Caucasians. However, limited examples of both antibodies greatly restricted broad investigations. Dombrock system antigens Do^a and Do^b appear to be poor stimulis and most examples of both antibodies rarely are found as a single specificity in a serum; and when detected, are notorious for disappearing in vivo. Antibodies within this system have been associated with weak to moderate transfusion reactions, but not with clinically defined cases of hemolytic disease of the newborn.

The Dombrock system remained a simple two allele system until 1992, when Banks et al. reported that the red cells of the rare Gy(a-) Hy(a-) Jo(a-) individuals were also Do(a-b-). Consequently, these three high incidences blood factors were included within the system. Interestingly, it had already been known that all Gy(a-) red cells lacked both Hy^a and Jo^a antigens and that Hy(a-) red cells lacked Jo^a antigens. Ironically, Swanson reported the first examples of both anti-Do^a (in 1965) and anti-Gy^a (1967) but as anti-Do^b was, at that time, yet to be discovered any association with Do^a and Gy^a could not be deduced.

These blood group antigens are carried on a glycosylphosphatidylinositol (GPI)-linked glycoprotein, but as of this date this system has not been associated with a defined chromosomal location.