Numerous methods exist for monitoring residual disease in multiple myeloma using peripheral blood, urine, and bone marrow (BM) techniques. This study was conducted in a cohort of 83 patients to compare residual disease detection using serum protein electrophoresis (SPE) and urine protein electrophoresis (UPE) with immunofixation with immunoperoxidase staining of BM tissue sections. Of the 83 patients, 49 had a positive SPE and/or UPE result and all had BM involvement shown by immunohistochemical analysis. The results for SPE and UPE were negative in 17 patients, and all 17 had a negative immunohistochemical BM result for a negative predictive value for SPE/UPE of 100%. In addition, SPE and UPE detected residual disease in 17 patients with negative BM biopsy studies. SPE and UPE can be used to screen patients for residual disease, and negative results for both can obviate the need for BM biopsy for the detection of residual disease by immunohistochemical analysis.