Evidence is presented that differences among serological specificities and in the structures of red cell antigens and antibodies fall naturally into two major categories, namely, macrodifferences and microdifferences. Examples are cited from the field of blood grouping, especially for the A-B-O, M-N, and Rh-Hr systems. It is demonstrated that macrodifferences usually relate to separate determinant groups in the antigen molecule, while sets of microdifferences may relate to one and the same determinant group, as with the cognate factors of Rho. To assume the existence of a one-to-one relationship between antibodies (and serological specificities) and determinant groups would require antigen molecules of finite size capable of accommodating an unlimited number of chemical determinant groups. It is pointed out that for each newly discovered specificity and antigen, it is important to determine whether one is dealing with a novel macro- or microdifference. The general applicability of the concept to fields other than blood grouping is pointed out.
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