The P blood group was identified by Landsteiner and Levine after they deliberately inoculated rabbits with human red cells in order to find new blood group factors. Since the resulting discovery of anti-P₁, a number of related antibodies have been identified, including anti-P, -P^k, -Tj^a, and -Luke (LKE). Some other antibodies, such as anti-IP₁, -iP₁, and -iP, require the specific Ii antigens, in combination with P antigens. Most of these antibodies are cold-reactive and thus are of little significance in transfusion. The Donath-Landsteiner antibody, a biphasic hemolysin, has been shown to have P specificity.

The biochemical nature of the antigens of the P blood group has been well defined. P system antigens are formed by the addition of carbohydrates to the fatty acid chain of sphingolipids. Because of the wide distribution of these antigens in nature, many of the antibodies to P system antigens result from immune response to other organisms. The Donath-Landsteiner antibody, found in cases of paroxysmal cold hemoglobinuria, has been thought to be such a response. Many cases of paroxysmal cold hemoglobinuria (PCH) in children are preceded by a flu-like illness or respiratory infection and are thought to be viral in nature. In adults, the Donath-Landsteiner antibody may appear in transient association with syphilis. It has been postulated that both the virus and spirochete carried a P-like carbohydrate structure that stimulates the autoantibody production. Recently, another virus, parvovirus B19, has been associated with the P blood group system. In healthy children, parvovirus B19 infection manifests itself with a malar rash while adult infection results in a mild flu-like illness. The persons at greatest risk of developing complications due to B19 are those with sickle cell disease and thalassemia.

The rare phenotype for this system is known as p [formerly Tj(a-)]. Soon after the discovery of this phenotype it was noted that the naturally occurring antibodies in p females were a cause of early abortion. Interestingly, the p phenotype is found more frequently in the Amish population.