A large (60-100%) negative interference in serum creatinine value of some (3 of 18 myeloma patients, all with monoclonal gammopathy of IgG type, was observed on several instruments that determine creatinine by the Jaffe reaction. No interference was observed in an enzymatic method. Serum electrophoresis showed a monoclonal band in all three samples. The interferent could be removed by acid precipitation or dithiothreitol preincubation, and partially isolated in the high molecular weight dialyzate from the serum. It was demonstrated that the interferent is not albumin or normal gammaglobulin. Kinetic analysis of the Jaffe reaction showed large initial decreases in absorbance, in agreement with the corresponding creatinine results. It is suggested that some monoclonal IgGs may react with the Jaffe picrate reagent, resulting in a false lowering of serum creatinine values.