These are antibodies found in one specie of animal (such as humans) which react against a component of another specie. The classic heterophile antibody is generated in humans infected systemically with the EB virus which gave us the Paul-Bunnell test, now adapted to various commercial monospot tests.

But, with the proliferation of immuno-based testing, patient heterophile antibodies can be found against essentially all of the animals (mouse [HAMA], rabbit, goat, sheep, pig, cow [bovine], rat, horse) now used to make reagents or tissue components for the various lab test systems. So, laboratorians and clinicians need to be alert to unexpected test results which might be due to heterophile antibodies. These can be at low to medium titers, but are commonly high titers. If the test is repeated by a method which has components from another animal, a negative test  result indicates that the initial positivity was due to a heterophile antibody. A heterophile titer is stable and does not rise or fall in that individual. Switching to a reagent not from the offending animal does not always help because there are animal-animal cross-reaction.

There has recently (2001-2003) been a high profile lawsuit related to failure to identify the cause of a highly elevated serum HCG as being due to a heterophile antibody. If, as with serum hCG, there is a corresponding urine test, a serum positive due to a heterophile antibody will have a negative urine test. [societal adverse impact of lawsuits]