Diagnosing ME/CFS requires a thorough medical history, physical and mental status examinations and laboratory tests to identify and exclude underlying or contributing conditions that have known treatment. Undiagnosed diabetes, low-thyroid and adrenal states, sleep apnea, severe depression, chronic sinus infections, anemia are examples of diseases that can cause prolonged fatigue.

In 1994, the U.S. Centers for Disease Control and Prevention (CDC) developed the following diagnostic criteria:
  1. Clinically evaluated, unexplained persistent or relapsing chronic fatigue over a period of 6 months that is of new of definite onset (i.e., not lifelong), is not the result of ongoing exertion is not substantially alleviated by rest, and results in substantial reduction in previous levels of occupational, educational, social or personal activities.
  2. Four or more of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-join pain without joint swelling or redness; headaches of a new type; pattern or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours. These symptoms must have persisted or recurred during six or more consecutive months of illness and must not have occurred prior to the fatigue.