Researchers in Norway believe Chronic Fatigue Syndrome (CFS), also known as ME, may be caused by a wayward immune system attacking the body.
The illness, the cause of which is uncertain and has no known cure, has attracted significant controversy.
A small study, reported in PLoS One, showed a cancer drug, which inhibited the immune system, relieved symptoms in some patients.
The ME Association said the findings were "very encouraging news".
Doctors in Norway stumbled across their first clue in 2004 when treating a patient with both Hodgkin's lymphoma, a cancer of the white blood cells, and CFS.
When she received cancer treatment, her fatigue symptoms improved for five months.
The latest study, carried out at the Haukeland University Hospital in Bergen, built on the previous discovery by testing 30 patients with CFS.
Half were given two doses of Rituximab, a cancer drug which eliminates a type of white blood cell, while the other half were given a fake treatment.
In those patients receiving the drug, 67% reported an improvement in a score of their fatigue levels. Just 13% showed any improvement in the sham group.
Øystein Fluge, an oncology consultant at the hospital, told the BBC: "There was a varied response: none, moderate, dramatic relief of all symptoms.
"Two had no recurrence [of their symptoms], their life was turned completely around very dramatically."
Their theory is that a type of white blood cell, B lymphocytes, are producing an antibody which attacks the body.
The drug wipes out the lymphocytes which in some cases may "reset the immune system", however, in other patients the fatigue symptoms would return when more B lymphocytes were made.
Mr Fluge said: "I think the fact that patients responded to treatment, improved cognitive function, fatigue and pain makes us believe we're touching one of the central mechanisms.
"But we're scratching at the surface, I would not characterise this as a major breakthrough."
The researchers are now investigating the effect of giving more doses over a longer period of time.
If their hunch is right it will throw up more questions, such as what is the immune system actually attacking and whether or not an actual test for CFS/ME be developed.
Dr Charles Shepherd, the UK ME Association's medical adviser, said: "The results of this clinical trial are very encouraging news for people with ME.
"Firstly, they help to confirm that there is a significant abnormality in immune system function in this disease.
"Secondly, they indicate that altering the immune system response in ME could be an effective form of treatment for at least a subset of patients.
"We now need further clinical trials of such anti-cancer agents to see if other research groups can replicate these findings."