It is very rare, but yes, it is possible to get mono (mononucleosis) more than once, either from the same virus reactivating or from a different virus causing similar symptoms.

How mono usually works

Mono is most often caused by the Epsteinā€‘Barr virus (EBV), which is extremely common ā€” most adults have been infected with EBV at some point, often without even knowing it. After the first infection, the virus stays in the body for life in a dormant (inactive) state, usually in certain white blood cells.

Because the immune system develops longā€‘lasting immunity, most people only get classic mono once in their life. After that, the body usually keeps the virus under control and prevents a full second bout of mono.

When mono can come back

Even though true reinfection with EBV is rare, a few things can make it seem like mono is happening again:

  • Virus reactivation ā€“ In some people (especially those with a weakened immune system), EBV can reactivate and cause monoā€‘like symptoms again, months or even years later. This is more common in people with conditions like HIV, organ transplants, or certain autoimmune diseases.
  • Different virus causing similar symptoms ā€“ Other viruses (like cytomegalovirus, CMV, or even some adenoviruses) can cause symptoms that look just like mono (fever, sore throat, swollen glands, fatigue). So, what feels like ā€œgetting mono twiceā€ might actually be a different infection mimicking mono.
  • Chronic fatigue or postā€‘viral syndrome ā€“ Some people who had mono go on to develop longā€‘lasting fatigue (similar to ME/CFS), which can feel like mono dragging on or coming back, even though EBV itself isnā€™t causing a new active infection.

How common is getting mono twice?

True, full mono episodes from EBV are very uncommon after the first infection. Most doctors will tell patients they are ā€œimmuneā€ after one bout, and for the vast majority, thatā€™s true.

However, in recent years, some clinicians and patient communities have noted that a small number of people do experience recurrent monoā€‘like illness, especially if they have ongoing immune issues or chronic stress. Itā€™s still considered rare, but not impossible.

What to watch for

If someone who already had mono starts having symptoms again, itā€™s important to see a doctor to find out why. Key signs that might suggest mono or a similar illness include:

  • Severe fatigue that doesnā€™t improve with rest
  • Fever and chills
  • Very sore throat, sometimes with white patches
  • Swollen lymph nodes (especially in the neck)
  • Swollen tonsils
  • Enlarged spleen or liver (can cause belly pain on the upper left side)
  • Rash, especially if certain antibiotics (like amoxicillin) were taken

What to do if symptoms return

  • See a healthcare provider ā€“ They can do blood tests (like EBV antibody panels, CBC, liver tests) to check if EBV is active again or if another virus or condition is causing the symptoms.
  • Avoid risky activities ā€“ If thereā€™s any chance of an enlarged spleen, avoid contact sports and heavy lifting until cleared by a doctor, because of the risk of spleen rupture.
  • Support the immune system ā€“ Getting enough sleep, eating well, managing stress, and treating any underlying health issues can help reduce the chance of EBV reactivating or other infections taking hold.

Bottom line

  • Most people only get mono once and are protected from another full episode.
  • True second episodes of mono are rare, but possible, especially with a weakened immune system or EBV reactivation.
  • Many ā€œsecond monoā€ cases are actually a different virus or a postā€‘viral fatigue state, not a true reinfection.
  • If symptoms return, itā€™s best to get checked by a doctor to figure out the exact cause.

Information gathered from public forums or data available on the internet and portrayed here.