Blood compatibility testing is conducted in a medical laboratory to identify potential incompatibilities between blood group systems in blood transfusion. It is also used to diagnose and prevent some complications of pregnancy that can occur when the baby has a different blood group from the mother. Blood compatibility testing includes blood typing, which detects the antigens on red blood cells that determine a person's blood type; testing for unexpected antibodies against blood group antigens (antibody screening and identification); and, in the case of blood transfusions, mixing the recipient's plasma with the donor's red blood cells to detect incompatibilities (crossmatching). Routine blood typing involves determining the ABO and RhD (Rh factor) type, and involves both identification of ABO antigens on red blood cells (forward grouping) and identification of ABO antibodies in the plasma (reverse grouping). Other blood group antigens may be tested for in specific clinical situations.

Blood compatibility testing makes use of reactions between blood group antigens and antibodies—specifically the ability of antibodies to cause red blood cells to clump together when they bind to antigens on the cell surface, a phenomenon called agglutination. Techniques that rely on antigen-antibody reactions are termed serologic methods, and several such methods are available, ranging from manual testing using test tubes or slides to fully automated systems. Blood types can also be determined through genetic testing, which is used when conditions that interfere with serologic testing are present or when a high degree of accuracy in antigen identification is required.

Several conditions can cause false or inconclusive results in blood compatibility testing. When these issues affect ABO typing, they are called ABO discrepancies. ABO discrepancies must be investigated and resolved before the person's blood type is reported. Other sources of error include the "weak D" phenomenon, in which people who are positive for the RhD antigen show weak or negative reactions when tested for RhD, and the presence of immunoglobulin G antibodies on red blood cells, which can interfere with antibody screening, crossmatching, and typing for some blood group antigens.

Blood compatibility testing is routinely performed before a blood transfusion. The full compatibility testing process involves ABO and RhD (Rh factor) typing; screening for antibodies against other blood group systems; and crossmatching, which involves testing the recipient's blood plasma against the donor's red blood cells as a final check for incompatibility. If an unexpected blood group antibody is detected, further testing is warranted to identify the antibody and ensure that the donor blood is negative for the relevant antigen. Serologic crossmatching may be omitted if the recipient's antibody screen is negative, there is no history of clinically significant antibodies, and their ABO/Rh type has been confirmed against historical records or against a second blood sample; and in emergencies, blood may be transfused before any compatibility testing results are available.

Blood compatibility testing is often performed on pregnant women and on the cord blood from newborn babies, because incompatibility puts the baby at risk for developing hemolytic disease of the newborn. It is also used before hematopoietic stem cell transplantation, because blood group incompatibility can be responsible for some cases of acute graft-versus-host disease.

Blood types are defined according to the presence or absence of specific antigens on the surface of red blood cells. The most important of these in medicine are the ABO and RhD antigens but many other blood group systems exist and may be clinically relevant in some situations. As of 2021, 43 blood groups are officially recognized.

People who lack certain blood group antigens on their red cells can form antibodies against these antigens. For example, a person with type A blood will produce antibodies against the B antigen. The ABO blood group antibodies are naturally occurring, meaning that they are found in people who have not been exposed to incompatible blood. Antibodies to most other blood group antigens, including RhD, develop after people are exposed to the antigens through transfusion or pregnancy. Some of these antibodies can bind to incompatible red blood cells and cause them to be destroyed, resulting in transfusion reactions and other complications.

Serologic methods for blood compatibility testing make use of these antibody-antigen reactions. In blood typing, reagents containing blood group antibodies, called antisera, are added to suspensions of blood cells. If the relevant antigen is present, the antibodies in the reagent will cause the red blood cells to agglutinate (clump together), which can be identified visually. In antibody screening, the individual's plasma is tested against a set of red blood cells with known antigen profiles; if the plasma agglutinates one of the red blood cells in the panel, this indicates that the individual has an antibody against one of the antigens present on the cells. In crossmatching, a prospective transfusion recipient's plasma is added to the donor red blood cells and observed for agglutination (or hemolysis) to detect antibodies that could cause transfusion reactions.