We have demonstrated Th2 clonal anergy as a consequence of partial T cell activation by immunogenic peptide and chemically fixed APC, as well as by altered peptide ligand and live antigen-presenting cells (APC). Either stimulation resulted in a profound inability of the T cells to proliferate upon restimulation with antigen and functional APC, a similar phenomenon to that found with Th1 cells. The anergic state was long lasting and was restricted to proliferation, since the T cells retained the ability to produce cytokines upon restimulation, albeit at slightly reduced levels. Th2 anergy induction was inhibited by cyclosporine A, but not by provision of exogenous costimulation or growth factors. The data presented unify Th1 and Th2 cells with regard to anergy and suggest that the fundamental control during anergy for both subsets is prevention of clonal expansion, thus blocking amplification of the immune response.