The first antibody in the Knops blood group was found in the serum of an O Rh negative woman who had been multiply transfused in previous surgeries. Her blood was incompatible with all O negative donor units tested until the blood bank technologist Margaret Helgeson, tested her own blood and found it compatible. Thus, in a report published in 1970, the antibody was named anti-Kn^a-Helgeson and the blood group called Knops. The Helgeson cells were used extensively to test other antibodies with previously unknown specificities. In 1978, another antibody was identified that was compatible with the Helgeson cells but not the Knops-negative cells and this was named McCoy (McC^a). The next antibody reported for the system was named after the first two antibody producers, ie. Swain and Langley, thus the designation Sl^a. The final antibody identified to a high frequency antigen in the Knops system was found in the serum of Mrs. York and was named Yk^a.

Because of the difficulty in working with these antibodies little attempt was made to characterize them biochemically until it was found that they were carried on a protein known as complement receptor type one (CR1). The CR1 protein has two other polymorphism in addition to the Knops blood group. These are a structural polymorphisms, ie. the protein exists in several sizes as well as an expression polymorphism where the number of molecules on the red blood cell varies from donor to donor. In 1997, CR1 was identified as one of the proteins involved in the rosetting of red cells infected with Plasmodium falciparum malaria to uninfected cells.

The rare type in the Knops system is the "Helgeson" phenotype, however, these cells do not totally lack CR1 but rather have extremely reduced copy numbers. Thus, this is only a serological null. The incidence has been reported to be 1 in 1,000 in Caucasians and 1 in 1,250 in African-Americans. Several Knops antigens show ethnic variability. For instance, McC^b is found almost exclusively in Africans (~50%) compared to Caucasians (<1%). The Sl(a-) phenotype, which has been postulated to protect against severe malaria, occurs in a frequency of 35-40% in African-Americans, but can be as high as 70% in West Africa. Molecular studies have found that most of the Knops System antigens are due to amino acid substitutions.