Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe post-exercise pain, fatigue, nausea, vomiting or other negative effects. Exercise intolerance is not a disease or syndrome in and of itself, but can result from various disorders.

In most cases, the specific reason that exercise is not tolerated is of considerable significance when trying to isolate the cause down to a specific disease. Dysfunctions involving the pulmonary, cardiovascular or neuromuscular systems have been frequently found to be associated with exercise intolerance, with behavioural causes also playing a part.

Exercise in this context means physical activity, not specifically exercise in a fitness program. For example, a person with exercise intolerance after a heart attack may not be able to sustain the amount of physical activity needed to walk through a grocery store or to cook a meal. In a person who does not tolerate exercise well, physical activity may cause unusual breathlessness (dyspnea), muscle pain (myalgia), tachypnoea (abnormally rapid breathing), inappropriate rapid heart rate or tachycardia (having a faster heart rate than normal), increasing muscle weakness or muscle fatigue; or exercise might result in severe headache, nausea, dizziness, occasional muscle cramps or extreme fatigue, which would make it intolerable.^{[citation needed]}

The three most common reasons people give for being unable to tolerate a normal amount of exercise or physical activity are:

Metabolic myopathies are inherited inborn errors of metabolism that affect the ability of the muscle to produce ATP, either aerobically (cellular respiration) or anaerobically (glycolysis and lactic acid fermentation). The common symptom that they share is exercise intolerance, due to the low ATP reservoir within muscle cells. Depending on the enzymatic or transport protein defect, symptoms may show only upon exertion or both at rest and upon exertion. Metabolic myopathies are further categorized by the system that they affect: inborn errors of carbohydrate metabolism (including muscle GSDs), inborn errors of lipid metabolism (fatty acid metabolism disorder), inborn error of purine–pyrimidine metabolism (such as AMP deaminase deficiency), and those involving enzymes or transport proteins within the mitochondrion (mitochondrial myopathies and disorders of citric acid cycle and electron transport chain). (See metabolic myopathies for more details.)

Cytochrome b mutations can frequently cause isolated exercise intolerance and myopathy and in some cases multisystem disorders. The mitochondrial respiratory chain complex III catalyses electron transfer to cytochrome c. Complex III is embedded in the inner membrane of the mitochondria and consists of 11 subunits. Cytochrome b is encoded by the mitochondrial DNA which differs from all other subunits which are encoded in the nucleus. Cytochrome b plays a major part in the correct fabrication and function of complex III.^{[citation needed]}

This mutation occurred in an 18-year-old man who had experienced exercise intolerance for most of his adolescence. Symptoms included extreme fatigue, nausea, a decline in physical activity ability and myalgia.^{[citation needed]}

Individuals with elevated levels of cerebrospinal fluid can experience increased head pain, throbbing, pulsatile tinnitus, nausea and vomiting, faintness and weakness and even loss of consciousness after exercise or exertion.^{[citation needed]}