Proinflammatory cytokines and adhesion molecules expressed by endothelial cells (ECs) play a critical role in initiating and promoting atherosclerosis. Agents that oppose these inflammatory effects in vascular cells include peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands, including 15-deoxy-δ<sup>12,14</sup>-prostaglandin J2 (15d-PGJ2) and synthetic thiazolidinediones. Recently, a new structural class of potent PPAR-γ agonists, 1,1-bis(3′-indolyl)-1-( p-substituted phenyl) methanes, has been characterized. The purpose of this study was to evaluate the anti-inflammatory effects of two PPAR-γ-active members of this class, 1,1-bis(3′-indolyl)-1-( p-t-butylphenyl)methane (DIM-C-pPhtBu) and 1,1-bis(3′-indolyl)-1-( p-biphenyl)methane (DIM-C-pPhC<sub>6</sub>H<sub>5</sub>), in ECs in vitro. Pretreatment of ECs with DIM-C-pPhC<sub>6</sub>H<sub>5</sub>, DIM-C- pPhtBu, or 15d-PGJ2 decreased tumor necrosis factor-α (TNF-α)-induced intercellular adhesion molecule (ICAM)-1 expression in a concentration-dependent manner. At a concentration of 10 µ M, DIM-C-pPhtBu and DIM-C-pPhC<sub>6</sub>H<sub>5</sub> decreased ICAM-1 expression by 77.5 and 71.3%, respectively, and comparable inhibition (84.4%) was observed for 10 µ M 15d-PGJ2 (p < 0.05). In contrast, 10 µ M ciglitazone and DIM-C-pPhCH<sub>3</sub>, which exhibits low PPAR-γ agonist activity, were inactive. The two new PPAR-γ agonists and 15d-PGJ2 also inhibited TNF-α-induced interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production in supernatants of TNF-α-stimulated ECs, whereas ciglitazone and DIM-C-pPhCH<sub>3</sub> did not decrease TNF-α-induced expression of these two proteins. This new structural class of PPAR-γ agonists inhibited the expression of ICAM-1 and the production of IL-6 and MCP-1 in TNF-α-activated ECs at lower concentrations than other synthetic PPAR-γ agonists, suggesting the potential clinical utility of 1,1-bis(3′-indolyl)-1-( p-substituted phenyl) methanes for decreasing endothelial inflammation.