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 γ (PPARγ)-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 PPARγ-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 α (TNFα) induction of plasminogen activator inhibitor type 1 expression. Here, we report NUR77 mRNA expression is increased in human vascular endothelial cells (HUVEC) stimulated by TNFα and that this effect is inhibited by a TZD in a PPARγ-independent manner. TZD treatment of HUVEC also inhibited the stimulatory effects of TNFα on NUR77 promoter activity, again in a PPARγ-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-κB)-binding site of the NUR77 promoter in HUVEC in a PPARγ-independent manner. In addition, TZD treatment also inhibited TNFα-mediated induction of NF-κB1 mRNA expression. Our results suggest a potential PPARγ-independent molecular mechanism for the anti-atherogenic effects of TZDs involving NF-κB-mediated transcriptional inhibition of cytokine-mediated induction of the orphan nuclear receptor NUR77 in HUVEC.