Causes & triggers

The short answer

Nobody yet knows exactly what causes ME/CFS. What we do know is that it usually starts with a trigger in someone who seems to have a genetic predisposition, and then something keeps the body stuck in an unwell state. Researchers call this the “why me, why now, why am I not getting better” question.

Triggers: what sets it off

Infections (the most common trigger)

Most people with ME/CFS can point to an infection when their illness began. Common ones include:

• Glandular fever (infectious mononucleosis), caused by the Epstein-Barr virus (EBV)
• COVID-19. Many people with Long COVID meet the criteria for ME/CFS.
• Influenza and other respiratory viruses
• Other infections, including Ross River virus, Q fever and giardia

A new infection is also a common trigger for a relapse in someone who had improved, and reinfection with COVID worsens fatigue and PEM in people who already have Long COVID.¹ That’s why infection avoidance is part of managing the illness.

Other reported triggers

Some people’s illness begins after surgery, a physical trauma, a period of severe stress, or pregnancy. Some can’t identify any trigger, and their illness came on gradually.

Who gets ME/CFS?

• Anyone can. It affects all ages, ethnicities and income levels, including children and teenagers.
• Women are affected about two to four times as often as men, a pattern shared with many immune-related illnesses. A Norwegian registry study found 3.2 women for every man, and about 4 in 5 DecodeME participants were women.^2,3
• Onset is most common in the teenage years and 30s to 40s.²
• Family history: ME/CFS is more common in relatives of people who have it.

Genetics: the DecodeME study

DecodeME is the largest genetic study of ME/CFS ever done. It compared DNA from more than 15,000 people with ME/CFS against about 260,000 people without it. The initial results were released as a preprint in August 2025 and are still awaiting peer review. Observational^3,4

It found:

• Eight regions of the genome linked to ME/CFS, mostly involving the immune system and nervous system, with a focus on neurons rather than supporting brain cells
• ME/CFS is polygenic: many genes each add a small amount of risk. No single gene causes it.
• One signal (near the CA10 gene) overlaps with chronic pain
• Only a tentative link to the HLA genes usually tied to classic autoimmune disease: a single HLA variant appeared protective and needs confirming. This suggests ME/CFS isn’t a typical autoimmune illness, though autoimmunity may matter in some subgroups.
• No shared genetic variants with depression or anxiety

A 2026 genetic analysis of 464 people followed after an infection in the Australian Dubbo study (a larger group than the original 2006 report of 253) agrees: a genetic tendency to depression did not predict who went on to develop post-infective fatigue.⁵

The next phase, Sequence ME & Long Covid, will read the full genomes of people with ME/CFS (from samples already given to DecodeME) and people with Long COVID. Current funding covers up to 6,000 samples, with the aim of reaching 9,000. It’s on our trials page.

What keeps it going?

This is the most active area of research. Several ideas fit together:

• A sickness response that won’t switch off. When you have an infection, your brain deliberately makes you tired, achy, foggy and sleepy so you rest. A 2025 review (Komaroff and Dantzer) proposed that in ME/CFS and Long COVID, neuroinflammation keeps these brain circuits locked in “sickness mode” after the infection has gone. Hypothesis⁶
• Problems with blood flow. Reduced blood flow to the brain, especially when upright, is common and measurable.
• An energy production problem. Cells switch to an inefficient backup way of making energy far too easily.
• Immune dysfunction. Including an ion channel called TRPM3 on immune cells that doesn’t work properly (Griffith University research),⁷ and autoantibodies in some patients.
• Viral reactivation. Viruses like EBV that stay in the body after the first infection may reactivate in some people.

These are explained in plain language on The science.

What does not cause ME/CFS

• Laziness, weakness or a lack of willpower
• Being unfit (deconditioning)
• “False illness beliefs.” This idea underpinned graded exercise and CBT-as-cure approaches, which are no longer recommended for ME/CFS.