Clonal anergy in Ag-specific CD4+ T cells is shown in these experiments to inhibit IL-2 production and clonal expansion in vivo. We also demonstrate that the defect in IL-2 gene inducibility can be achieved in both naive and Th1-like memory T cells when repeatedly exposed to aqueous peptide Ag. Nevertheless, this induction of clonal anergy did not interfere with the capacity of naive T cells to differentiate into Th1-like effector cells, nor did it prevent such helper cells from participating in T-dependent IgG2a anti-hapten responses and delayed-type hypersensitivity reactions. Thus, clonal anergy can contribute to the development of Ag-specific immune tolerance by limiting the size of a Th cell population, but not by disrupting its effector function.