Renal impairment and polyclonal hypergammaglobulinemia may abnormally increase the serum free light chain (sFLC) ratio, giving false-positive results with current reference intervals. We measured sFLCs with concomitant serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) in 281 patients. Results were interpreted relative to renal function (serum creatinine concentrations) and polyclonal hypergammaglobulinemia. Overall, 78 plasma cell disorders (PCDs) were detected with the serum panel of SPEP/sFLC vs 76 with SPEP/UPEP. In 13 samples with negative SPEP/UPEP, mildly increased ratios up to 3.1 (normal, 0.26-1.65) were observed: 10 were associated with increased serum creatinine and 1 with polyclonal hypergammaglobulinemia; 2 were unassociated with either condition. In 2 samples, decreased kappa/lambda ratios were identified that were clinically significant despite normal SPEP/UPEP. Two monoclonal gammopathies were identified with UPEP and sFLC, but samples were normal with SPEP. Screening for PCDs with a serum panel consisting of SPEP and the sFLC assays is a highly sensitive approach that could eliminate the need for UPEP. A mildly increased kappa/lambda ratio up to 3.1 was observed with increased serum creatinine and/or polyclonal hypergammaglobulinemia that was consistent with pathophysiologic changes, and, therefore, renal reference intervals are recommended.