The cytokine tumor necrosis factor-a (TNF-α) plays an important role in endothelial injury, which is associated with the release of reactive oxygen species and the induction of apoptosis. We report on our study of TNF-α-induced apoptosis in human coronary artery endothelial cells and its modulation by the peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand pioglitazone. Treatment of cells with TNF-α (40 ng/mL) resulted in apoptosis as measured by DNA laddering and caspase-3 activation. TNF-α treatment decreased the expression of antiapoptotic protein Bcl-2 (P < .05 vs control), but not the expression of Fas or FLIP, in human coronary artery endothelial cells. Treatment of cells with TNF-α also enhanced lipid peroxidation (P < .01 vs control). Pretreatment of cells with the PPAR-γ ligand pioglitazone blocked TNF-α-mediated apoptosis, caspase-3 activation, expression of Bcl-2, and lipid peroxidation (P < .01 vs TNF-α alone). These results indicate that TNF-α induces oxidative stress in human coronary artery endothelial cells, resulting in apoptosis through a reduction in Bcl-2 expression and the subsequent activation of caspase-3. The PPAR-γ ligand pioglitazone modulates lipid peroxidation, alters Bcl-2 expression and caspase-3 activation, and finally reduces apoptosis. The antioxidant and antiapoptotic effects of pioglitazone may be the mechanism by which this agent reduces endothelial injury.