The thiazolidinediones (TZDs) have been reported to reduce atherogenesis in preclinical models and atherosclerosis in clinical trials in pre-diabetic and diabetic patients. Although peroxisome proliferator-activated receptor I? (PPARI?)-mediated effects on gene expression have been thought responsible for this effect, a complete understanding of the molecular mechanisms responsible remains to be fully elucidated. We have previously reported PPARI?-independent modulation of NUR77 (also known as Nr4a1), an orphan nuclear receptor deemed important in the atherogenic process, in association with TZD-mediated inhibition of tumour necrosis factor I? (TNFI?) induction of plasminogen activator inhibitor type 1 expression. Here, we report NUR77 mRNA expression is increased in human vascular endothelial cells (HUVEC) stimulated by TNFI? and that this effect is inhibited by a TZD in a PPARI?-independent manner. TZD treatment of HUVEC also inhibited the stimulatory effects of TNFI? on NUR77 promoter activity, again in a PPARI?-independent manner, confirming the transcriptional nature of this effect. TZD treatment also attenuated the binding of nuclear proteins to the nuclear factor kappa B (NF-I?B)-binding site of the NUR77 promoter in HUVEC in a PPARI?-independent manner. In addition, TZD treatment also inhibited TNFI?-mediated induction of NF-I?B1 mRNA expression. Our results suggest a potential PPARI?-independent molecular mechanism for the anti-atherogenic effects of TZDs involving NF-I?B-mediated transcriptional inhibition of cytokine-mediated induction of the orphan nuclear receptor NUR77 in HUVEC. A? 2011 Society for Endocrinology.