In previous studies, we demonstrated that patients with active systemic lupus erythematosus (SLE) had significantly decreased percentages of circulating CD4+2H4+ suppressor/inducer cells. The decrease in this T cell subset was most frequent and most marked in patients with active SLE and renal disease. In the present study, we attempted to determine whether SLE patients had plasma antilymphocyte antibodies preferentially reactive with the CD4+2H4+ subset. We found that many SLE patients did have these specifically reactive antibodies. Furthermore, the presence of anti-lymphocyte antibodies reactive with CD4+2H4+ cells correlated with disease activity in these patients. Also, in vitro functional studies revealed that suppressor/inducer function was eliminated in the pokeweed mitogen–driven IgG synthesis system after the treatment of CD4 cells with patient plasma antilymphocyte antibodies and complement. These results suggest that antilymphocyte antibodies play a role in the elimination of CD4+2H4+ cells in patients with active SLE.