Landsteiner and Wiener used blood from a monkey (Macacus rhesus) to immunize rabbits and guinea pigs in order to define new antibody specificities. One of the antibodies they produced appeared to have the same specificity as a human antibody found in several woman who had stillborn fetuses. Consequently, the antibodies were named anti-Rh for rhesus. However, as early as 1942 it was known that the rabbit/guinea pig and human antibodies could not be the same. When the guinea pig antibody was used to test Rh+ and Rh negative cord blood cells (as defined by the human antibody) all samples were reactive. The guinea pig antibody was given the name "D-like". Then Race and Sanger found two women whose antibodies could be absorbed by Rh negative red cells and which appeared to be similar to the "D-like" antibody from animals. Following further studies by Levine the "D-like" name was changed to LW in honor of Landsteiner and Wiener.

Today the LW and D antigens still remain related. Rh+ red cells express LW more strongly than Rh negative cells. The early nomenclature tried to accommodate this observation by using a numerical system; eg. LW₁, LW₂, etc. but this changed following Sistonen's report of a new low frequency antigen called Ne^a which was found in ~5% of Finns. Because further work suggested that the Ne^a gene was allelic to LW, they were renamed LW^a and LW^b (Ne^a). Thus, the null phenotype for this system would be LW(a-b-) which is extremely rare and is the result of a partial gene deletion. A transient or acquired form of LW(a-b-) has been reported and these individuals are found because they produce a transient anti-LW. Some (but not all) examples have been associated with terminal illnesses such as Hodgkin's disease, leukemia, sarcomas or other malignancies.

Investigations of red cell membrane proteins using both human and murine monoclonal antibodies have shown that these antigens are carried on a 40,000 molecular weight glycoprotein. The cDNA work has revealed that the LW protein contains 208 extracellular amino acids, 21 amino acids spanning the membrane and 12 amino acids inside the membrane. There are several sites for the attachment of carbohydrate complexes. The LW glycoprotein is a member of the immunoglobulin gene superfamily and is also known as ICAM-Y.