Suppressor of cytokine signaling (SOCS)-1 is a member of a family of proteins that negatively regulate cytokine signaling pathways. We have previously established that SOCS-1 is a key regulator of IFN-γ signaling and that IFN-γ is responsible for the complex inflammatory disease that leads to the death of SOCS-1-deficient mice. In this study, we provide evidence that SOCS-1 is also a critical regulator of IFN-γ-independent immunoregulatory factors. Mice lacking both SOCS-1 and IFN-γ, although outwardly healthy, have clear abnormalities in their immune system, including a reduced ratio of CD4: CD8 T cells in lymphoid tissues and increased expression of T cell activation markers. To examine the contribution of TCR Ag specificity to these immune defects, we have generated two lines of SOCS-1-deficient mice expressing a transgenic TCR specific for an exogenous Ag, OVA (OT-I and OT-II). Although TCR transgenic SOCS-1−/− mice have a longer lifespan than nontransgenic SOCS-1−/− mice, they still die as young adults with inflammatory disease and the TCR transgenic SOCS-1−/− T cells appear activated despite the absence of OVA. This suggests that both Ag-dependent and-independent mechanisms contribute to the disease in SOCS-1-deficient mice. Thus, SOCS-1 is a critical regulator of T cell activation and homeostasis, and its influence extends beyond regulating IFN-γ signaling.