Many autoimmune diseases are associated in Caucasians with HLA-B8 and/or HLA-DR3 antigens. There is evidence that bearers of these antigens may display significant changes in immune parameters when compared to individuals not having these antigens. Recently, increased numbers of blood activated T lymphocytes have been reported in the majority of these diseases. The increase in activated blood T lymphocytes is paradoxically characterized by an in vitro impairment of T cell activation. Particularly, an inadequate production of interleukins has been observed. We have studied blood levels of activated T cells in HLA-typed, healthy subjects. The results show that the percentage of activated T cells, as recognized by monoclonal antibodies anti-CD25, anti-Ia and anti-MLR3, was more frequent in HLA-B8, DR3 positive individuals. On the other hand, in the 24 h, PHA stimulated cultures IL-2, IFN-gamma and the percentage of T cells CD25 positive were decreased. Thus, there was an apparent discrepancy between the increase of blood activated T cells and the in vitro impaired T cell activation. Since there is evidence that HLA-B8, DR3 positive subjects are genetically low responders, a possible reason for the discrepancy might be their relative inability to remove antigenic stimuli from the body. In this case, the increased number of activated blood T cells may reflect a cellular activation caused by persistent antigenic stimulation.