Fatigue can be a symptom of hundreds of medical conditions. All other possible causes of fatigue will be ruled out before chronic fatigue syndrome (CFS) is diagnosed. Examinations and tests are used to rule out the most likely causes of fatigue, depending on the person's medical history and symptoms.

Chronic, persistent fatigue may be a symptom of various conditions, including:

• Fibromyalgia. Although fibromyalgia and CFS can have similar symptoms, people who have fibromyalgia tend to have more muscle pain and more specific tender points than people who have CFS. In contrast, the main symptom of CFS is overwhelming fatigue.
• Lyme disease.
• Depression or anxiety.
• Infectious mononucleosis (mono).
• Multiple sclerosis (MS) or myasthenia gravis.
• Anemia.
• Diabetes.
• Insomnia.
• Sleep apnea.
• Hypothyroidism.
• Lupus.
• Rheumatoid arthritis.
• Infectious diseases, such as hepatitis, syphilis, or human immunodeficiency virus (HIV) infection.
• Certain types of cancer (lymphoma, leukemia).
• Neurasthenia, or nervous exhaustion, a disease marked by intense nervous irritability and weakness.
• Multiple chemical sensitivity disorder, a controversial diagnosis of an allergy-like sensitivity to an unusually broad range and number of substances. This condition has not been subjected to rigorous scientific scrutiny, and there is considerable doubt as to whether it actually exists.

Other possible causes of fatigue include:

• Stress.
• Medicine side effects, or medicines changed or added too quickly.
• Alcohol or drug abuse.
• Too little exercise or excessive exercise (overtraining).