Interferon-gamma and interleukin-4 (IL-4) induce distinct gene expression profiles in macrophages by differentially activating signal transducers and activators of transcription (STAT)1 and STAT6, respectively. The role of suppressor of cytokine signaling (SOCS)-1 as a negative regulator of IFN-gamma signaling is well established. However, its potential role as a negative regulator of IL-4 signaling has not been explored. We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent, whereas induction of SOCS-1 by IFN-gamma is STAT1-dependent. Unlike their common ability to induce expression of SOCS-1, IL-4 also induced expression of SOCS-2 but not SOCS-3 in macrophages, whereas IFN-gamma induced expression of SOCS-3 but not SOCS-2. Forced expression of SOCS-1 or SOCS-3, but not SOCS-2, inhibited activation of STAT6 by IL-4. Moreover, SOCS-1 appears to serve as an endogenous regulator of IL-4 signaling in macrophages because the magnitude and duration of STAT6 activation as well as IL-4-mediated gene expression were much greater in SOCS-1-deficient (SOCS-1(-/-)) macrophages than in wild-type macrophages. Our findings demonstrate that, like IFN-gamma, IL-4 also induces expression of SOCS-1 in macrophages, and SOCS-1 feedback inhibits expression of STAT6-responsive genes.