A number of classes of endogenous antibodies, including heterophile, rheumatoid factor, and autoantibodies, can interfere with immunoassay measurements of many different analytes. Heterophile and rheumatoid factor antibody interferences have been described previously for the AxSYM cardiac troponin I assay. Several commercial products have been developed to neutralize heterophile antibody interferences. We describe a patient with multiple apparently falsely elevated cardiac troponin I results that were unique to the AxSYM analyzer. These cardiac troponin I results diluted linearly. When treated with 2 different heterophile-blocking reagents, the magnitudes of the falsely elevated results increased 17- and 26-fold, and these results also demonstrated dilution linearity. This interfering substance could be removed by passage through an immobilized protein A column and by polyethylene glycol precipitation. It does not appear to be a classic heterophile antibody, nor is it a paraprotein. Laboratorians must remain constantly vigilant for immunoassay interferences that lead to clinically significant inaccurate results and must recognize that accepted methods for detecting and neutralizing the interference may be ineffective.