Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is involved in controlling metabolism, cell growth, inflammatory responses and tumorigenesis. Specific PPAR-gamma agonists, such as rosiglitazone, inhibit growth and induce differentiation in several different cancer cell lines including liver cancer cells. Lycopene has been shown to decrease the initiation of hepatic preneoplastic foci induced by diethylnitrosamine (DEN) in rats. Recently, we showed that apo-10’-lycopenoic acid, an enzymatic metabolite of lycopene, suppresses carcinogenesis in a mouse model. However, the underlying mechanism(s) is not well defined. In the present study, we examined the effects of apo-10’-lycopenoic acid treatment on cell growth and apoptosis, as well as PPAR-gamma activation in both human liver cells and in livers of ob/ob mice treated with DEN. We reported that apo-10’-lycopenoic acid dose-dependently increased the mRNA expression and protein levels of PPAR-gamma in human THLE-2 liver cells. Apo-10’-lycopenoic acid (from 5 µM to 20 µM) produced concentration-dependent increases in luciferase activity, as compared with PPAR-gamma agonist rosiglitazone in cells co-transfected with constructs containing PPAR-gamma and PPRE-luciferase reporter construct. Additionally, apo-10’-lycopenoic acid dose-dependently inhibited cell growth and induced apoptosis in THLE-2 liver cells by stimulating the cyclin-dependent kinase inhibitor p21 and by reducing activation of c-Jun NH2-terminal kinase (JNK) and cyclin D1 gene expression. However, human HepG2 liver cancer cells were less sensitive to apo-10’-lycopenoic acid treatment, as compared with THLE-2 cells. We further examined the effect of apo-10’-lycopenoic acid treatment (120 mg/Kg diet) in ob/ob mice administered intraperitoneally with a single-dose of DEN (30 mg/Kg body weight). After eight weeks, we found lower expression of PPAR-gamma but higher levels of tumor necrosis factor-alpha and phosphorylated JNK in the liver of ob/ob mice injected with DEN, as compared with controls. Furthermore, apo-10’-lycopenoic acid supplementation prevented DEN-down-regulated expression of PPAR-gamma in the liver of ob/ob mice and significantly inhibited DEN-induced expression of proliferating cell nuclear antigen and cyclinD1. In addition, apo-10’-lycopenoic acid supplementation inhibited DEN-induced tumor necrosis factor-alpha expression and JNK activation in the liver of ob/ob mice. Together, our findings indicate that apo-10’-lycopenoic acid produced from lycopene metabolism may function as a natural ligand of PPAR-gamma and as a potential chemopreventive agent against hepatic tumorigenesis.