Tumor Necrosis Factor alpha (TNF) is a multifunctional cytokine that has been implicated as a causative factor in obesity-linked insulin resistance. It is commonly accepted that macrophage derived TNF acts in a paracrine manner on adjacent adipocytes to inhibit the expression of various adipocyte genes and to attenuate insulin signaling. Several studies have revealed that STAT 5 proteins are modulated during adipogenesis and can modulate the transcription of some adipocyte genes. In this study, we demonstrate that TNF treatment of 3T3-L1 adipocytes also results in the rapid turnover of STAT5A and STAT5B in a process that is independent of STAT5 activation by tyrosine phosphorylation. In addition, STAT5B is more labile than STAT5A under these conditions, suggesting that the C-terminus of STAT5 may be involved in the turnover of each protein. Initial characterization of TNFmediated degradation of STAT5 indicates that inhibition of the proteasome stabilizes both forms of STAT5 in the presence of TNF. In addition, inhibition of NF-B activation stabilizes STAT5A in the presence of TNF, indicating TNF mediated degradation of STAT5 proteins may involve the NF-B pathway. STAT5 proteins are abundantly expressed in mature adipocytes and are normally extremely stable proteins under a wide range of conditions. However, our results demonstrate that the potentiation of TNF -mediated signaling is associated with a significant increase in the degradation of STAT5 proteins in 3T3-L1 adipocytes.