Immunoglobulin light chain (AL) amyloidosis is a rare clonal plasma cell disorder with high rate of missed diagnosis, misdiagnosis and mortality. Conventional assays, such as serum immunofixation electrophoresis (IFE) and serum free light chain (FLC) assay, are unable to accurately detect low concentrations of monoclonal protein (M protein), especially as a patient’s renal function deteriorates. The heavy/light chain (HLC) assay, a relatively new method, can quantify intact immunoglobulins in serum and has proven to be valuable in the diagnosis and monitoring of multiple myeloma (MM). However, there is limited research on its application in AL amyloidosis. In this study, we evaluate the value of HLC assay in AL amyloidosis patients at different disease stages, and compare it to the performance of IFE and FLC assay. Among 40 untreated patients, 34 (85%) were positive for IFE, 34 (85%) had an abnormal free light chain ratio (FLCr), and 31 (78%) had an abnormal heavy light chain ratio (HLCr). Among 67 serum samples obtained from 44 treated patients, 57 (85%) were positive for IFE, 9 (13%) had abnormal FLCr, and 45 (67%) had abnormal HLCr. There were 1 (14%) of 7 patients in complete response (CR), 17 (68%) of 25 patients in very good partial response (VGPR), 9 (82%) of 11 patients in partial response (PR) and 6 (75%) of 8 patients in no response (NR) showed an abnormal HLCr. Our findings identified the potential value of the HLC assay in the detection of M proteins and response and serologic residual disease monitoring.