People without Rh factor on the surface of their blood cells are Rh-negative and have Rh incompatibility with blood that is Rh-positive. This incompatibility means that when exposed to Rh-positive blood more than once, the immune systems of people with Rh-negative blood produce antibodies to destroy the Rh-positive blood cells.

Pregnancy and blood transfusions are the two most common ways that a person with Rh-negative blood can be exposed to Rh-positive blood.

In a woman with Rh-negative blood who has been exposed at least once to Rh factor (usually from a previous pregnancy), this immune system response can cause serious problems during a future pregnancy if the fetus has Rh-positive blood. The mother's immune system produces Rh antibodies that cross the placenta and attack the fetal blood cells. This can be prevented by giving the mother an injection of antibodies, called RhoGAM.

People requiring blood transfusions have Rh testing and are given only compatible blood.