Immunosenescence is characterized by decreases in protective immune responses and increases in inflammation and autoimmunity. The T helper (Th)17 subset of cluster‐of‐differentiation (CD)4 T cells, which is identified by its generation of interleukin (IL) ‐17, is implicated in autoimmune pathogenesis. To elucidate immunosenescent changes in Th17 cell cytokines, splenic CD4 T cells from 22‐ to 24‐month‐old (old) mice and 6‐ to 10‐wk‐old (young) mice were incubated on anti‐CD3 plus anti‐CD28 (anti‐T cell antigen receptor) antibodies. After 96 h, T cells of old C57BL/6 and CBA mice generated up to 20‐fold more IL‐17 and up to 3‐fold more IL‐6 than those of young mice; T cells of young mice generated up to 5‐fold more IL‐21 than those of old mice;and no difference was found for IFN‐γ. At 24 h, cytokine mRNA levels paralleled 96 h cytokine concentrations. Naive CD4 T cells from old mice incubated on anti‐T cell antigen receptor antibodies with transforming growth factor‐β, IL‐1, IL‐6, and IL‐23 to induce de novo differentiation of Th17 cells had more IL‐17 mRNA and produced more IL‐17 than those of young mice. BAY11–7082 and the phytochemicals triptolide and butein suppressed nuclear concentrations of nuclear factor‐κB and secreted levels of IL‐17, IL‐21, and IFN‐γ in parallel, with greater potency in Th17 cells from young than old mice. Pharmacological correction of altered generation of Th17 cell cytokines in immunosenescence represents a novel therapeutic approach to aging‐induced inflammatory diseases.—Huang, M.‐C., Liao, J‐J., Bonasera, S., Longo, D. L., Goetzl, E. J. Nuclear factor‐κB‐dependent reversal of aging‐induced alterations in T cell cytokines. FASEB J. 22, 2142–2150 (2008)