Most people will only get mono once, but the infection can make a comeback in rare cases.

Mono is a viral infection that causes symptoms like fatigue, swollen lymph nodes, and a severe sore throat. These symptoms usually get better within two to four weeks. Sometimes, fatigue and other symptoms may continue for three to six months or more.

It’s incredibly rare for mono to return after the first infection. When the virus does reactivate, it usually doesn’t cause symptoms. That said, symptoms are still possible.

Keep reading to learn more about why recurrence happens, symptoms to watch for, other conditions that may be to blame, and more.

Most cases of mono result from an infection with the Epstein-Barr virus (EBV). EBV spreads from person to person through saliva — which is why mono is often called the “kissing disease” — and other body fluids.

EBV is so common that most people will contract the virus at some time in their lives. Many people will never experience any symptoms.

High school and college students are most likely to contract EBV and subsequently develop mono. About 1 in 4 teens and young adults who contract EBV for the first time will go on to develop infectious mononucleosis, according to the Centers for Disease Control and Prevention.

Once you contract EBV, the virus stays in your body for the rest of your life. The virus remains behind in your immune cells and tissue. Your doctor can find the virus by testing your blood for antibodies, but the virus usually remains dormant. This means that you likely won’t experience symptoms after your first contact with the virus.

The virus may be more likely to reactivate and cause symptoms in people who have a weakened immune system. This includes people who:

  • are pregnant
  • have had an organ transplant
  • have HIV or AIDS

It’s also possible to catch a form of mono that’s caused by a different virus, such as cytomegalovirus (CMV). If you have EBV, you can still develop mono caused by another virus.

You’re more likely to experience recurrence if you have a weakened immune system.

If you have a healthy immune system, immune cells called natural killer (NK) cells and T cells work to kill EBV-infected cells in the blood.

People who have defects in their NK and T cells aren’t able to kill off the virus as well. And in some cases, even a healthy immune system can be overwhelmed by the virus. When this happens, high levels of EBV remain in the blood.

If your symptoms persist for three to six months — or return three to six months after you first had mono — it’s known as chronic active Epstein-Barr virus infection.

Chronic active EBV infection is more common in people from:

  • Asia
  • South America
  • Central America
  • Mexico

You can help reduce your risk for EBV by avoiding close contact with anyone who has mono.

You shouldn’t kiss or share personal items, like toothbrushes, with people who you know have mono or are otherwise sick.

If you’ve contracted EBV and go on to develop mono, there’s no way to prevent it from coming back. Still, it’s rare for mono to return.

Symptoms of mono usually appear four to six weeks after you’ve contracted EBV.

They can include:

  • severe fatigue
  • fever
  • sore throat
  • headache
  • body aches
  • swollen lymph nodes in your neck
  • swollen tonsils

Symptoms like fever and sore throat should go away within a couple of weeks. You may experience fatigue and swollen lymph nodes for a few more weeks.

In some cases, fatigue can last for months.

Persistent fatigue may be a sign of chronic EBV infection. See your doctor if your fatigue lasts for more than a month after mono has been diagnosed.

Your doctor can look for other signs of chronic EBV infection, including:

  • swollen lymph nodes
  • fever
  • enlarged spleen
  • enlarged liver
  • low numbers of infection-fighting immune cells in your immune system
  • low numbers of blood-clotting cells called platelets

Given how rare it is to get mono twice, it’s more likely that your symptoms are due to another condition.

Myalgic encephalomyelitis (ME), formerly known as chronic fatigue syndrome, is often mistaken for mono. Fatigue is one of the hallmark symptoms of both illnesses. And like mono, ME can cause a sore throat and swollen lymph nodes.

Tiredness can last for many months after a mono infection, and several studies have led some experts to conclude that EBV causes ME. One study found that in pediatrics following mono infection, 9-12% developed chronic fatigue syndrome. More research is needed to confirm this connection.

Other conditions that cause mono-like symptoms include:

Strep throat is a bacterial infection of the throat. In addition to the symptoms of mono, strep throat can cause:

  • red and swollen tonsils
  • white patches on the tonsils
  • red spots on the back of the roof of the mouth
  • nausea
  • vomiting
  • fine, sandpaper-like rash

Influenza (flu) is a viral infection of the respiratory tract. In addition to the symptoms of mono, the flu can cause:

  • chills
  • runny or stuffy nose
  • cough

Cytomegalovirus (CMV) is another common virus. It affects people of all ages. Although its symptoms are similar to that of mono, it doesn’t cause a sore throat.

Hepatitis A is a viral infection of the liver. In addition to the symptoms of mono, hepatitis A can cause:

  • nausea
  • vomiting
  • belly pain
  • jaundice, or yellowing of the skin and whites of the eyes
  • appetite loss
  • dark urine
  • joint pain
  • itching

Rubella is a viral infection that causes a rash. In addition to the symptoms of mono, rubella can cause:

  • redness or swelling in the whites of the eyes
  • runny nose
  • cough
  • red rash that starts on the face then spreads

If you’re still experiencing a severe sore throat, swollen lymph glands in your neck, and fatigue after a few days of treatment, see your doctor. They can assess your progress and adjust your treatment plan as needed.

Seek immediate medical attention if you have:

  • difficulty breathing
  • difficulty swallowing
  • fever of 101.5 °F (38.6 °C) or higher
  • severe headache
  • stiff neck
  • yellow color to your eyes or skin
  • sharp pain in your left side
  • abdominal pain