In this report we show that two widely-used monoclonal antibodies, TAL-1B5 and DA6.147, which react with the HLA-DR alpha chain on immunoblots, recognize the C-terminal intracellular tail of this HLA-DR subunit. We demonstrate that both MoAbs react with a synthetic peptide representing the intracellular C-terminal tail of the DR alpha chain and that mutant DR molecules lacking this part of the alpha chain lose reactivity with TAL-1B5 and DA6.147, both in Western blot analysis and in intracellular FACS staining.