Objective— Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily involved in the growth and differentiation of many cell types. Although the activation of PPARγ in human vascular smooth muscle cells (VSMCs) inhibits the growth of these cells, the precise mechanism of this effect is unknown. PPARγ-mediated growth inhibition of VSMCs is associated with the induction of the differentiated phenotype. A zinc finger transcription factor, GATA-6, has been implicated in the maintenance of the differentiated phenotype in VSMCs. Methods and Results— The administration of 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), a naturally occurring PPARγ ligand, and troglitazone, a thiazolidinedione derivative, induced the expression of smooth muscle myosin heavy chain and smooth muscle α-actin, highly specific markers for differentiated VSMCs. Stimulation of proliferative VSMCs with PPARγ ligands also increased the activity of the transfected wild-type smooth muscle myosin heavy chain promoter but not that of the mutant promoter, in which a GATA-6 binding site was mutated. Compatible with the role of GATA-6, both 15d-PGJ 2 and troglitazone upregulated the DNA binding activity of GATA-6 in proliferative VSMCs. Conclusions— The activation of PPARγ-dependent pathways induces the differentiated phenotype in proliferative VSMCs, and this induction is mediated, in part, through a GATA-6–dependent transcriptional mechanism.