In 1950, the Duffy blood group was named for the multiply transfused hemophiliac whose serum contained the first example of anti-Fy^a. In 1951, the antibody to the antithetical antigen, Fy^b, was discovered in the serum of a woman who had been pregnant three times. Using these antibodies three common phenotypes were defined: Fy(a+b+), Fy(a+b-), and Fy(a-b+). Differences in the racial distribution of the Duffy antigens were discovered four years later when it was reported that the majority of Blacks had the erythrocyte phenotype Fy(a-b-). This phenotype is exceedingly rare in Whites. The frequency of the Fy(a-b-) phenotype is 68 percent in American Blacks and 88-100 percent in African Blacks. The molecular basis for the Fy(c-b-) phenotype is the result of a point mutation in the erythroid specific promoter. The absence of Duffy antigens on erythrocytes results in their resistance to invasion by two malaria parasites, Plasmodium vivax and Plasmodium knowlesi. This racial variation in distribution of the Duffy system antigens provides one of the few known examples of selective advantage conferred by a blood group phenotype.

The Duffy genes, located on chromosome one at position 1922-23, have recently been cloned and sequenced. The difference between Fy^a and Fy^b is a change in the amino acid at position 43 from aspartic acid (Fy^a) to glycine (Fy^b). Studies have shown that blacks whose erythrocytes express Fy^b antigen also have the antigen on the cells of their kidney, heart, muscle, brain and placenta. The Duffy gene codes for a protein known as a chemokine receptor, which is important in the inflammatory process. Accordingly, the Fy protein is also known as DARC (Duffy Antigen Receptor for Chenokines).