Macroamylasemia is a benign acquired condition, characterized by a serum amylase unusually large in molecular size that has been found to occur in apparently healthy humans as well as in a variety of diseases including liver disease, diabetes, cancer malabsorption and autoimmune disorders. Most commonly macroamylasemia results from the formation of immune complexes between amylase and immunoglobulins. We describe the first case of an association between macroamylasemia/hyperamylasemia and rheumatoid arthritis characterized by the absence of immunoglobulins, as amylase binding globulins, within the macroamylase complex. Failure to identify macroamylase as the cause of unexplained but benign hyperamylasemia correctly, can lead to costly studies (e.g. ultrasonography, computerized tomography) to rule out pancreatic disease, and could induce prescription of unnecessary elemental diets and replacement therapies, as reported in our patient.