Tumor necrosis factor-α (TNF-α) is elevated in obesity and in acute inflammatory states, and contributes to the elevated plasminogen activator inhibitor-1 (PAI-1) levels associated with these conditions. Mice genetically deficient in the p55 and p75 TNF-α receptors were used to study the roles of these receptors in the expression of PAI-1 in obese (ob/ob) mice, and in lean mice following acute stimulation with TNF-α. In ob/ob mice, p55 and p75 tumor necrosis factor-α receptors (TNFRs) act cooperatively to induce PAI-1 mRNA in most tissues, including the adipose tissue, kidney, heart, and liver. However, in lean mice, TNF-α-induced PAI-1 expression is mediated primarily by the p55 TNFR. Interestingly, PAI-1 mRNA expression in all tissues of the TNF-α-treated p75-deficient lean mice was significantly higher than that observed in TNF-α-treated wild-type mice. These observations suggest that the p75 TNFR may play a role in attenuating TNF-α-induced PAI-1 mRNA expression in acute inflammatory conditions. Our observation that soluble p75 TNFR was elevated in the plasma of TNF-α-treated mice in comparison to untreated mice supports this hypothesis. These studies thus provide insights into the TNF-α receptors involved in mediating and modulating the expression of PAI-1 in acute and chronic (eg, obesity) inflammatory states associated with elevated TNF-α.