Suppressor of cytokine signaling-1 (SOCS-1) is an inhibitory protein that regulates responses to cytokines. Previously, we have shown SOCS-1 to be a key inhibitor of interferon gamma (IFNgamma). Recent data suggest that SOCS-1 may regulate other cytokines in vivo, in addition to IFNgamma. Uncontrolled responses to interleukin-12 (IL-12), an inflammatory cytokine, could contribute to increased IFNgamma production and the development of inflammatory disease in SOCS-1(-/-) mice. Here, we assess responses of SOCS-1-deficient cells to IL-12. Both IL-12-induced T cell proliferation and NK cytotoxic activity are enhanced in SOCS-1-deficient cells, relative to controls. To examine the contribution of continued IL-12 signaling to the SOCS-1(-/-) disease, we generated mice lacking both SOCS-1 and signal transducer and activator of transcription 4 (STAT4), an essential component of the IL-12 signaling pathway. SOCS-1(-/-) STAT4(-/-) mice have improved survival relative to SOCS-1(-/-) mice, but die between 1 and 2 months of age. We conclude that, in addition to IFNgamma, SOCS-1 regulates responses to IL-12.