Cancer chemopreventive agents transcriptionally induce glutathione S-transferase (GST), which can protect cells from chemical-induced carcinogenesis. Activation of either NF-E2-related factor-2 (Nrf2) or the CCAAT/enhancer binding protein-β (C/EBPβ) contributes to GST induction. Peroxisome proliferator-activated receptor-γ (PPARγ) and the retinoic acid X receptor (RXR) play roles in regulating cell differentiation and chemoprevention. This study examined GSTA2 gene induction by the PPARγ activator and 9-cis-retinoic acid (RA), a RXR ligand, and investigated the molecular basis of PPAR-RXR-mediated GSTA2 induction in the H4IIE hepatocytes. Either 15-deoxy-δ (12, 14)-prostaglandin J₂ (PGJ₂) or RA induced GSTA2 with Nrf2 and C/EBPβ activation. When compared with PGJ₂ or RA alone, PGJ₂ + RA enhanced GSTA2 induction, with increases in Nrf2 and C/EBPβ activation. PGJ₂ + RA increased the luciferase reporter gene activity in the cells transfected with the −1.65-kb flanking region of the GSTA2 gene. Thiazolidinedione PPARγ agonists, troglitazone, rosiglitazone, and pioglitazone, in combination with RA, potentiated GSTA2 induction, confirming that the activation of the PPARγ and RXR heterodimer contributed to GSTA2 expression. Deletion of the antioxidant response element- or C/EBP-binding sites or the overexpression of dominant-negative mutant of C/EBP abolished the reporter gene expression. PGJ2 + RA increased the binding of the PPARγ − RXR heterodimer to the putative PPAR-response elements (PPREs) in the GSTA2 promoter. Specific mutations of these multiple PPRE sites resulted in the complete loss of its responsiveness to PGJ2 + RA, which suggests that these binding sites function as a PPRE-responsive enhancer module (PPREM). Transactivation of PPREM by the PPARγ − RXR heterodimer was verified by the effective GSTA2 induction in the cells treated with PGJ2 + RA after transfecting them with the plasmids encoding PPARγ1 and RXRα. In conclusion, the PPARγ − RXR heterodimer promotes GSTA2 induction by activating PPREM in the GSTA2 gene, as well as inducing Nrf2 and C/EBPβ activation.