Investigators in the United Kingdom have shown that hereditary amyloidosis can be misdiagnosed as Ig light-chain (AL) amyloidosis because family history is an ineffective screen, and tissue staining used to type amyloid is unreliable. Misdiagnosis of AL can lead to inappropriate use of chemotherapy and failure to diagnose a hereditary disease. Over a 3-year period we sought to determine how often both possible sources of amyloidosis occurred in the same patient. We employed an algorithm based on established data and patterns of amyloidosis in order to focus the screening effort. Of 178 consecutive patients referred for amyloidosis, 54 were screened by polymerase chain reaction techniques with primers designed to detect transthyretin, apolipoprotein AI, apolipoprotein AII, fibrinogen Aalpha, and lysozyme variants. Three patients (6% of those screened and 2% of symptomatic patients) had both a monoclonal gammopathy and a hereditary variant. These results justify further study of screening for hereditary variants in patients with apparent AL, and highlight the need for practical techniques for identifying fibrils extracted from tissue.