Abstract Suppressor of cytokine signaling 1-deficient (SOCS1−/−) mice, which are lymphopenic, die <3 wk after birth of a T cell-mediated autoimmune inflammatory disease characterized by leukocyte infiltration and destruction of vital organs. Notably, Foxp3+ regulatory T cells (Tregs) have been shown to be particularly potent in inhibiting inflammation-associated autoimmune diseases. We observed that SOCS1−/− mice were deficient in peripheral Tregs despite enhanced thymic development. The adoptive transfer of SOCS1-sufficient Tregs, CD4+ T lymphocytes, or administration of SOCS1 kinase inhibitory region (KIR), a peptide that partially restores SOCS1 function, mediated a statistically significant but short-term survival of SOCS1−/− mice. However, the adoptive transfer of SOCS1-sufficient CD4+ T lymphocytes, combined with the administration of SOCS1-KIR, resulted in a significant increase in the survival of SOCS1−/− mice both short and long term, where 100% death occurred by day 18 in the absence of treatment. Moreover, the CD4+/SOCS1-KIR combined therapy resulted in decreased leukocytic organ infiltration, reduction of serum IFN-γ, and enhanced peripheral accumulation of Foxp3+ Tregs in treated mice. These data show that CD4+/SOCS1-KIR combined treatment can synergistically promote the long-term survival of perinatal lethal SOCS1−/− mice. In addition, these results strongly suggest that SOCS1 contributes to the stability of the Foxp3+ Treg peripheral population under conditions of strong proinflammatory environments.