Alpha-2 macroglobulin is a large plasma protein found in the blood. It is produced by the liver, and is a major component of the alpha-2 band in protein electrophoresis.

Alpha-2 macroglobulin levels are increased in nephrotic syndrome, a condition where the kidneys start to leak out some of the smaller blood proteins. Because of its size, α2-macroglobulin is retained in the bloodstream. Increased production of all proteins means α2-macroglobulin concentration increases. This increase has little adverse affect on the health, but is used as a diagnostic clue. Longstanding chronic renal failure can lead to amyloid by alpha-2 macroglobulin (see main article: amyloid).

A rare variant (polymorphism) of α2-macroglobulin leads to increased risk of Alzheimer's disease, although the mechanism is unknown.