α₂-macroglobulin assay is of major significance in the differential diagnosis of nephrotic syndrome, where an elevated α₂-macroglobulin:albumin ratio is indicative of postrenal hematuria. In patients with liver cirrhosis and diabetes, the level of α₂-macroglobulin is found to be elevated.

In hyperfibrinolytic states, after major surgery, in septicemia and severe hepatic insufficiency, the measured levels of α₂-macroglobulin are often low. Patients with acute pancreatitis exhibit low serum concentrations that correlate with the severity of the disease.