Mice lacking the gene for suppressor of cytokine signaling 1 (SOCS1) show defective homeostasis of T lymphocytes due to accumulation of CD8(+) T cells, resulting at least partly from dysregulated IL-15 signaling. IL-15 alone does not stimulate proliferation of naïve CD8 T cells, but can synergize with IL-21 to induce proliferation, suggesting a potential role for IL-21 in the defective homeostasis of CD8(+) T lymphocytes in SOCS1(-/-) mice. Since IL-21 strongly induced SOCS1 mRNA in CD8(+) T cells, we investigated whether SOCS1 regulates their response to IL-21. CD8(+) T cells isolated from SOCS1-deficient mice proliferated vigorously in response to IL-21+IL-15. In CD8(+) T lymphocytes expressing transgenic TCR, IL-21+IL-7 provided a stronger stimulus to naïve cells whereas IL-15+IL-21 potently stimulated memory cells. Compared to truly naïve or memory cells, SOCS1(-/-) H-Y TCR(+) CD8(+) T cells displayed CD44(lo)Ly6C(hi)CD122(int)CD127(lo) partial memory phenotype and exhibited stronger response to IL-15+IL-21 than truly naïve cells. In SOCS1(-/-) CD8(+) T cells, IL-21 caused greater reduction in IL-15 threshold for activation in a dose-dependent manner. SOCS1 deficiency did not modulate IL-21Ralpha expression or sensitivity to IL-21, but delayed the loss of IL-21-induced phospho-STAT3 signal. These results show that SOCS1 is a critical regulator of IL-21 signaling in CD8(+) T cells, and support the notion that sustained IL-21 signaling might also contribute to the aberrant T cell homeostasis in SOCS1-deficient mice.