Subacute combined degeneration of the spinal cord is a result of Vitamin B12 deficiency. Lack of this vitamin is often caused by pernicious anemia, an autoimmune blood disorder that prevents absorption of Vitamin B12. Although symptoms of anemia are the most common manifestation of this disorder, subacute combined degeneration can also occur without such symptoms.

While Vitamin B12 deficiency can rarely be caused by diet (Vegans, who eat no dairy or meat products, are most susceptible), the most common cause is an inability to absorb the vitamin from the intestines.

Subacute combined degeneration primarily affects the spinal cord, but it can also include damage to the brain, the nerves of the eye, and the peripheral (body) nerves. The damage is diffuse. Initially, there is damage to the myelin sheath (the covering of the nerve that speeds transmission of nerve impulses), followed by destruction of the axon portion of the cell and eventually, destruction of the entire nerve cell. The mechanism by which lack of B12 damages nerves is not clear. It is thought that lack of this vitamin causes an abnormal formation of fatty acids, which are used by the body to build cell membranes and the nerve myelin sheath.

Risks include lack of dietary B12 (rare), inherited or acquired lack of the factor needed to absorb B12 from the intestines, antibodies to this factor (pernicious anemia) which prevents its absorption, and disorders of the small intestine, such as Crohn's disease as well as other malabsorptive conditions which can occur after gastrointestinal surgery.