Serum protein electrophoresis (SPE) demonstrates a monoclonal protein as an M spike in the majority of patients with monoclonal gammopathies. However, in patients with an apparently normal SPE pattern or hypogammaglobulinemia, immunofixation electrophoresis (IFE) can reveal an M protein. We undertook this study to determine the yield of reflex IFE testing in patients with hypogammaglobulinemia and to identify any laboratory or biochemical parameters that would predict a positive IFE result. We evaluated 380 patients with hypogammaglobulinemia and a normal SPE pattern. Of 380, 37 (9.7%) had a positive IFE result in serum, urine, or both. Of the other laboratory values evaluated, a high alpha2-globulin level with an increased alpha2-globulin/alpha1-globulin ratio, a low hemoglobin level, and an elevated creatinine level predicted a positive IFE result. There was a 2-fold increase in the odds ratio for a positive IFE result when the alpha2-globulin/alpha1-globulin ratio was elevated. We recommend reflex IFE testing in patients with hypogammaglobulinemia with a normal SPE pattern if any of the following are present: elevated alpha2- globulin/alpha1-globulin ratio, low hemoglobin level, and elevated creatinine level.