The reason why obesity (a chronic low-grade inflammatory disease) is associated with low levels of sex hormone-binding globulin (SHBG) remains to be elucidated. The present study provides evidence that TNFα (a proinflammatory cytokine increased in obesity) reduces SHBG production by human HepG2 hepatoblastoma cells. Although the human SHBG promoter contains one nuclear factor-κB (NF-κB) binding site, the human SHBG promoter activity did not change after TNFα treatment or transfection with either small interfering RNA against p65 or a p65 expression vector in luciferase reporter gene assays. The effect of TNFα on human SHBG expression was indirect, and it was mediated by NF-κB through the down-regulation of hepatocyte nuclear factor (HNF)-4A: a key SHBG transcriptional regulator. Furthermore, the HNF-4A proximal promoter contains three putative NF-κB binding sites. The HNF-4A promoter activity was decreased by the treatment with TNFα or the transfection of a p65 expression vector, and it was increased by the treatment with small interfering RNA against NF-κB in luciferase reporter gene assays. Finally, the TNFα treatment promotes the NF-κB binding to the HNF-4A promoter in chromatin immunoprecipitation assays. We conclude that sustained exposition to elevated levels of TNFα decreases SHBG production by reducing hepatic HNF-4α levels via NF-κB activation in HepG2 cells. © 2012 by The Endocrine Society.