Paternity blood testing was first performed in the middle half of the twentieth century by comparing blood types of tested parties. This involved isolation of blood sera from antigen-challenged individuals that did not possess certain red blood cell antigens. These antigens are protein molecules that may be combined with sugar molecules and reside in the red blood cell membrane. These sera cause coagulation of red blood cells in individuals that possess that particular red blood cell antigen. In the ABO blood typing system, humans can possess the A antigen (A blood type), the B antigen (B blood type), both the A and B antigen (AB blood type), or neither of these antigens (O blood type). Red blood cell antigen systems of this sort can be used for paternity testing because there are genes that code for the antigens and these are inherited genes. A mother who has Type B blood and a father who has Type O blood could not have a child who has type AB blood. The true father of the child must have the gene for the A antigen. Using RBC antigen systems for paternity testing did not provide for a very powerful test because the frequencies of the genes that coded for the antigens are not very low.
In the 1970s a more powerful test using white blood cell antigens or Human Leukocyte Antigens (HLA) was developed. This produced a test that was able to exclude about 95 percent of falsely accused fathers. Several milliliters of blood are required to perform the test. Blood types can not be used to determine who the father is; however, blood types can be used to determine the biological possibility of fatherhood.