Sixty-six giant cell lesions ranging from inflammatory to neoplastic were evaluated for HLA-DR antigens using formalin/paraffin tissue and a monoclonal antibody labelled by the avidin-biotin peroxidase. HLA-DR antigens were expressed in nearly all lesions, predominantly on round, macrophage-like cells. Granulomatous inflammatory lesions were generally more immunoreactive than non-inflammatory lesions. Multinucleate giant cells were relatively unreactive in non-inflammatory lesions as compared to inflammatory lesions. Determination of HLA-DR expression does not appear to be helpful in discriminating between the various giant cell lesions.