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In most cases, mononucleosis (mono) is a result of infection with the Epstein-Barr virus (EBV). Another type of virus called cytomegalovirus (CMV) sometimes causes mono, but this is rare. After initial exposure to the virus, a person develops immunity (protection against future infection) to it. However, the virus remains in a dormant state in the body for a lifetime and it may occasionally reactivate. This does not cause symptoms of infection, although it may expose others to the virus.

The disease itself is transmitted through infected saliva. People may become infected through the transfer of saliva during open-mouth kissing. Mono can also be spread as the result of sharing food, beverages, eating utensils, straws, toothbrushes, cosmetics or pillows. People may also inhale droplets spread by infected patients who sneeze or cough. However, mono is not spread as easily as other common respiratory infections (e.g., colds, the flu, strep throat).

People can become infected with the virus that causes mono at any age. However, adolescents and young adults have an increased risk of developing symptoms of mono. This is because children exposed to the virus often develop no symptoms or very minor symptoms that go unnoticed. It is only when first exposure to the virus occurs after childhood that symptoms of mono develop. Many children may not be exposed to the virus until their teens or as a young adult, and thus it is adolescents and young adults who are most likely to experience symptomatic mono. By the age of 40, most adults in the United States have already been exposed to the virus and are immune from infection.

People who receive blood transfusions and bone marrow transplants may have an increased risk of contracting mono, although these routes of transmission are rare.