People with CFS/ME may improve after a few months, after many years, or never at all. They may reach a plateau at some constant level of health, or may progressively decline. Often, the symptoms change over time, or cycle irregularly. Relapses are common, especially after stressful life events or additional illness. Exertion can cause not merely a relapse, but a worsening of overall health. Undiagnosed cases of CFS/ME often worsen as the sufferer attempts to return to a "normal" level of activity, only to make their condition worse through exertion.

Of those CFS/ME patients moderately to severely affected, many may expect to remain so for an indeterminate period, even for the duration of their life. It is not known whether any patients truly "recover" entirely from the illness, or merely recuperate enough to regain previous levels of activity. Few patients report a total "cure".

CFS/ME can prove to be fatal, as in the case of Sophia Mirza from the UK, where the coroner recorded a verdict of:

"Acute anuric renal failure due to dehydration arising as a result of CFS/ME".

The pathologist said,

"ME describes inflammation of the spinal cord and muscles. My work supports the inflammation theory. There was inflammation in the basal root ganglia."

It should be noted that inflammation of the "muscles" is erroneous, as opposed to the spinal cord inflammation, as this has never been a criteria for a ME diagnosis.

CFS/ME has been linked to heart damage and cardiac arrest among other causes of death. Research has not yet progressed to determine whether this is in fact the case, and some patients die from co-morbid diseases.