Addison disease affects approximately 11 to 14 in 100,000 people of European descent. The autoimmune form of the disorder is the most common form in developed countries, accounting for up to 90 percent of cases.

The cause of autoimmune Addison disease is complex and not completely understood. A combination of environmental and genetic factors plays a role in the disorder, and changes in multiple genes are thought to affect the risk of developing the condition.

The genes that have been associated with autoimmune Addison disease participate in the body's immune response. The most commonly associated genes belong to a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders (such as viruses and bacteria). Each HLA gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign proteins. The most well-known risk factor for autoimmune Addison disease is a variant of the HLA-DRB1 gene called HLA-DRB1*04:04. This and other disease-associated HLA gene variants likely contribute to an inappropriate immune response that leads to autoimmune Addison disease, although the mechanism is unknown.

Normally, the immune system responds only to proteins made by foreign invaders, not to the body's own proteins. In autoimmune Addison disease, however, an immune response is triggered by a normal adrenal gland protein, typically a protein called 21-hydroxylase. This protein plays a key role in producing certain hormones in the adrenal glands. The prolonged immune attack triggered by 21-hydroxylase damages the adrenal glands (specifically the outer layers of the glands known, collectively, as the adrenal cortex), preventing hormone production. A shortage of adrenal hormones (adrenal insufficiency) disrupts several normal functions in the body, leading to hypoglycemia, hyponatremia, hypotension, muscle cramps, skin hyperpigmentation and other features of autoimmune Addison disease.

Rarely, Addison disease is not caused by an autoimmune reaction. Other causes include infections that damage the adrenal glands, such as tuberculosis, or tumors in the adrenal glands. Addison disease can also be one of several features of other genetic conditions, including X-linked adrenoleukodystrophy and autoimmune polyglandular syndrome, type 1, which are caused by mutations in other genes.