We compared a new serum immunoassay for quantitation of serum free light chains (FLC) with the conventional tests for clonal immunoglobulin production: bone marrow immunohistochemistry, serum immunofixation electrophoresis, and urine immunofixation electrophoresis. Serum samples from 169 patients with AL amyloidosis and 20 controls were examined. Elevated levels of kappa-FLC and lambda-FLC were found in 94% and 93% of patients with the respective clonal disease. However, false positive elevations of kappa-FLC and lambda-FLC were found in 30% and 44% of patients with clonal disease of the other light chain subtype. We found that the FLC level was a reliable test for the diagnosis of clonal disease when the FLC kappa:lambda ratio was abnormal and was comparable to the conventional tests in patients with AL amyloidosis. After a histologic tissue diagnosis of amyloidosis, determining the type as AL amyloidosis relies on a panel of hematologic tests to determine light chain clonality and the exclusion other forms of amyloidosis.