HLA-DR antigens show restricted tissue distribution in comparison with the more extensive expression of HLA class I molecules. This constitutive expression is genetically controlled by well-defined mechanisms. In addition, DR antigen expression can be induced by a variety of cytokines through different molecular genetic events that convert DR-negative epithelia into positive cells. In this review we analyse the two major pathological situations in which abnormal DR expression occurs: autoimmune diseases and tumour development. We hypothesize that conversion to DR-positivity may produce two opposite effects in both clinical situations: (1) a useful one in tumours associated with a good prognosis; and (2) a harmful one in autoimmune diseases with increased tissue damage.