BACKGROUND: Historically, classification of U‐ and U variant (U+var) individuals has been made by hemagglutination and adsorption and elution studies performed with polyclonal U antisera. Molecular studies and serologic tests with a potent monoclonal anti‐He have shown that U+var red cells, some of which are He+, possess an altered form of glycophorin B. STUDY DESIGN AND METHODS: Seventeen sera, previously determined to contain anti‐U, were tested with a panel of red cells of common and rare MNS types. RESULTS: Five sera contained anti‐U only, and 12 sera contained broadly reactive antibodies with apparent, but inseparable, anti‐U,He or anti‐U,N,He specificities. CONCLUSION: The majority of antibodies produced by S‐s‐U‐ individuals are anti‐U plus anti‐glycophorin B and are analogous to the broadly reactive antibodies produced by En(a‐) individuals whose red cells lack glycophorin A or have altered glycophorin A. To avoid further immunization of patients with anti‐U, sera used for classification of S‐s‐U‐ donors should be selected to detect S‐s‐ red cells that possess altered forms of glycophorin B.