Skp2 is frequent amplified and overexpressed in breast cancer, making it a potential molecular target for cancer therapy. The objective of this study was to examine the effect of PPARγ overexpression on Skp2 expression in breast cancer cell lines. First, we investigated the role of PPARγ and Skp2 in human breast cancer progression. Immunohistochemical analysis of 70 specimens on formalin-fixed paraffin sections was performed. Furthermore in vitro, Western blot analysis was used to study the relationship between PPARγ and Skp2. We found that the expression of PPARγ and Skp2 expression was inverse correlation whether in vivo or in vitro. In addition, PPARγ overexpression can down-regulate the expression of Skp2 mRNA and protein in breast cancer cells. PPARγ overexpression decreased breast cancer cell proliferation and induced spontaneous apoptosis even in the absence of exogenous ligand. These PPARγ-overexpressing cells were dramatically more sensitive to PPARγ ligand-induced apoptosis compared with parental or Myc-control transfected cells. Overexpressing of Skp2 partially reversed PPARγ's pro-apoptotic and anti-proliferative abilities. These results suggested that PPARγ's pro-apoptotic and anti-proliferative abilities appear to be triggered at least in part by the modulation of Skp2.