The first description of an antibody in the Lewis system was published in 1946 by Mourant. Lewis system antibodies are some of the most frequently encountered in pre-transfusion or pre-natal screening. Anti-Le^a is the most frequent antibody in the Lewis system, is often naturally occurring and is of the IgM class. Anti-Le^b exists in two forms: one reacts only with Le(b+) cells of the A₂ or O type (anti-Le^bH) while the other reacts with all Le(b+) cell regardless of ABO type.

The antigens of the Lewis system are carbohydrate (sugar) determinants carried either on proteins or lipids. Although they were first detected on red cells, the majority of the biochemical studies have been performed on Lewis substances isolated from plasma or saliva. Generally in both Caucasians and Blacks, the three major phenotypes are Le(a+b-), Le(a-b+) and Le(a-b-). These arise through the interaction of two genes- Lewis and secretor. If a Lewis gene is present the donor will be either Le(a+b-) or Le(a-b+); however, if there is no Lewis gene the red cells type as Le(a-b-). In Blacks the Le(a-b-) type occurs with a frequency of 20-25% as compared to 5% in Caucasians. Furthermore, red blood cells from newborns will type as Le(a-b-) regardless of their genetic makeup as the cells have not had time to absorb Lewis antigens from the plasma. Another type which is extremely rare in Caucasians and Blacks, ie. Le(a+b+), is found in the Oriental population and appears to be due to a weak secretor gene.

In 1993, Boren et al. reported that the bacteria Helicobacter pylori used the fucose sugar found in the Le^b antigen as a receptor to establish infection. H. pylori has been implicated as the causative agent in gastritis, peptic ulcers and gastric carcinoma. Several studies suggest that transplant patients having the Le(a-b-) phenotype have shorter transplant survival times than those who have a Lewis gene. Interestingly, antibodies raised to cancer cells often have specificity within the Lewis blood group.