SOCS proteins take part in a classical negative feedback loop to attenuate cytokine signaling. Although STAT family members positively modulate Socs gene expression, little else is known about Socs gene regulation. Here, we identify functional binding sites for GFI-1B, a proto-oncogenic transcriptional repressor, in the promoters of murine Socs1 and Socs3. Thus, mutating these sites relieved transcriptional repression, as determined by luciferase reporter assays of transiently transfected erythropoietin-responsive 32D-EpoR and HCD57 cells. Furthermore, cotransfection of Gfi-1B expression plasmid repressed reporter activity of wild-type (but not mutagenized) Socs1 and Socs3 promoters, strongly suggestive of direct GFI-1B binding to these promoters. In addition, overexpression of Gfi-1B resulted in reduced transcript levels of Socs1 and Socs3, but not Socs2 or Cis. Upon stimulation with erythropoietin, Socs transcripts were rapidly induced, whereas Gfi-1B mRNA was down-regulated. Interestingly, the latter effect appears to rely on STAT5 activity, but not on phosphoinositide 3-kinase or MAPK pathways. Thus, cytokine-mediated STAT5 activation allows relief of direct repression by GFI-1B of the Socs1 and Socs3 promoters, but apparently not of the Socs2 and Cis promoters. This constitutes a previously undescribed mode of controlling cytokine responsiveness, through the direct repression of a tumor suppressor (SOCS1) by a proto-oncoprotein (GFI-1B).