Lung cancer is one of the most common malignant tumors in the world, and is the leading cause of cancer death in men and women in the United States. Despite recent advances in understanding the molecular biology of lung cancer and the introduction of multiple new chemotherapeutic agents for the treatment of non-small cell lung cancer, the dismal <15% 5-year survival rate has not changed substantially. New approaches toward the treatment and prevention of this disease are therefore clearly indicated. In many studies, peroxisome proliferator-activated receptor (PPAR)-γ has been implicated in the regulation of cell growth and differentiation. In our studies, we have shown that the PPAR-γ ligands 15d-PGJ2, ciglitazone, and troglizaone inhibited the growth of several human lung cancer cell lines and induced apoptosis. Wy14643, one PPAR-α agonist, had no effect on those processes. The cell cycle control cyclin-dependent kinase inhibitor P21waf1/Cip1 plays a role in cancer cell cycle arrest and apoptosis. In order to determine if effects on P21 explain the human lung cancer growth inhibition observed with PPAR-γ ligands, we examined the effects of these agents on P21 expression. We showed that treatment of lung cancer cells with PPAR-γ ligands 15d-PGJ2, ciglitazone, and troglizaone induced P21 messenger RNA and protein levels, and reduced cyclin D1 messenger RNA levels as compared to the control. These effects were PPAR-γ specific because WY14643 did not affect P21 expression. The PPAR-γ antagonist GW9662 inhibited the effect of ciglitazone and troglitazone, but not that of 15d-PGJ2 on P21 gene expression. P21 antisense oligos inhibited both basal and PPAR-γ ligands induced p21 messenger RNA and protein levels. Transient transfection assays indicated that PPAR-γ ligands increased P21 promoter activity in human lung cancer cells. Gel mobility shift assay showed that PPAR-γ ligands increased surfactant protein-1 binding activity in the P21 promoter region. Taken together, our results indicate that PPAR-γ ligands inhibit human lung cancer cell growth and induce apoptosis by inducing the cyclin-dependent kinase inhibitor P21, and reducing cyclin D1 genes expression in PPAR-γ–dependent and –independent pathways.